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Pneumococcal Disease & Vaccine Information


Pneumococcal & Pneumococcal Vaccine Quick Facts

Pneumococcal (S. Pneumoniae) 

pneumococcal
Image source: CDC PHIL
  • Pneumococcal disease is a bacterial infection caused by S. pneumoniae (Streptococcus pneumoniae). It is the most common cause of bacterial pneumonia and middle ear infection (otitis media) in the U.S., and is the third most frequent cause of bacterial meningitis.1 Pneumococcal bacteria are often found in the upper area of the throat behind the nose in about 5 to 90 percent of healthy individuals.2 However, when pneumococcal bacteria cause invasive infection, serious complications can lead to inflammation of the brain, blood infections, pneumonia and death.3
  • Symptoms of pneumococcal infection include sudden onset of fever and fatigue, sneezing and cough with mucus and shortness of breath. The infection may start with a general feeling of being unwell, a low-grade fever and a cough that doesn’t include mucus before symptoms worsen. Symptoms of pneumococcal meningitis (brain inflammation) include stiff neck (inability to touch the chin to chest without moderate to severe pain in the back of the neck and head); headache; extreme fatigue or seizures. Symptoms of otitis media include a painful ear, red or swollen eardrum, fever, and irritability.4 
  • Pneumococcal bacteria are primarily transmitted through respiratory secretions by coughing and sneezing.5  Persons most at risk of developing invasive pneumococcal disease include immunocompromised individuals, smokers, persons with chronic cardiac, lung, or kidney disease, individuals without a spleen, and persons with cochlear implants or a cerebrospinal fluid leak. Children attending daycare are also at a higher risk.6
  • Otitis media, often referred to as a middle ear infection, is commonly caused by S. pneumoniae and remains the most common pediatric infection requiring treatment by the age of 12 months. Over 60 percent of children will experience at least one episode of acute otitis media prior to the age of one. S. pneumoniae is the leading cause of bacterial meningitis in children under the age of five. Pneumococcal pneumonia, the most common infection caused by S. pneumoniae in adults, is estimated to cause over 400,000 hospitalizations each year in the United States. 36 percent of all community acquired pneumonias are caused by S. pneumoniae. 7 
  • Globally, 16 percent of deaths worldwide in children under 5 are related to pneumonia, with most deaths occurring in sub-Saharan Africa and south Asia.8 In the United States, the CDC combines the death rates of pneumonia with influenza and estimates it to be the eighth leading cause of deaths in persons 65 years of age or older.9 In 2017, there were 19,620 reported cases of invasive S. pneumoniae in the U.S., with 1,220 cases occurring in children under the age of five.10

Pneumococcal Vaccine 

  • There are two types of pneumococcal vaccines licensed for use in the U.S. today: Pneumovax 23, a pneumococcal polysaccharide vaccine (PPSV23) manufactured by Merck, and Prevnar 13, a pneumococcal conjugate vaccine (PCV13) manufactured by Wyeth (Pfizer) pharmaceuticals. PPSV23 contains 23 strains of pneumococcal and is approved for use in adults 50 and older and in children 2 and older who are at an increased risk for pneumococcal disease.11 PCV13) vaccine contains 13 strains of pneumococcal and is approved for the prevention of otitis media and invasive disease caused by S. pneumoniae in children between 6 weeks and 5 years of age. It is also approved for the prevention of invasive disease caused by S. pneumoniae in children between 6 and 17 years and for the prevention of pneumonia and invasive disease caused by S. pneumoniae in adults 18 years of age and older.12 
  • The CDC recommends four doses of pneumococcal conjugate vaccine (PCV13) for infants and children, with a dose given at 2, 4, 6 and between 12 and 18 months of age. Children between 2 and 18 years who are at a higher risk of invasive pneumococcal disease are also recommended to receive one dose of PPSV23 at least 8 weeks following the most recent dose of PCV13. A second dose of PPSV23 is recommended at least 5 years following the first dose in children who are immunocompromised, HIV-positive, have sickle cell disease, or who lack a functioning spleen.13 PPSV23 and PCV13 are also recommended for use in immunocompromised children, adults, and seniors.14 15
  • All adults 65 years of age and older are recommended by the CDC to receive one dose of PPSV23. PCV13 can also be considered for use in healthy seniors 65 years and older but routine vaccination is no longer recommended. This recommendation was revised at the June 2019 Advisory Committee on Immunization Practices (ACIP) when data presented found limited benefit to vaccinating all seniors with PCV13 vaccine.16
  • According to the CDC, PCV7, the original pneumococcal conjugate vaccine, resulted in a 97 percent decrease in invasive pneumococcal disease caused by the 7 pneumococcal strains found within the vaccine.17 However, the mass use of PCV7 vaccine by American children put pressure on some of the nearly 90 additional pneumococcal strains known to cause invasive disease resulting in an increased rate of otitis media from by serotypes not included in the seven-valent vaccine.18 19 In an attempt to prevent 6 additional pneumococcal strains from causing invasive disease, PCV13 vaccine was developed to replace PCV7.20 Current research indicates that while PCV13 has significantly decreased nasopharyngeal colonization with the serotypes found within the vaccine, replacement with non-vaccine type strains continues. New vaccines to target emerging strains of pneumococcal not covered in the current vaccines are currently in clinical trials.21 22
  • Reported pneumococcal vaccine reactions include fever, severe local reactions (swelling, redness, and pain at site of injection), irritability, drowsiness, restless sleep, vomiting, diarrhea, rash, decreased appetite, convulsions, asthma, pneumonia and sudden infant death syndrome (SIDS).23 24
  • Using the MedAlerts search engine, as of May 31, 2019, there have been 21,536 serious adverse events reported to the Vaccine Adverse Events Reporting System (VAERS) in connection with pneumococcal vaccinations (PCV7, PCV13, PPSV23). Over 60 percent of these reported serious pneumococcal vaccine-related adverse events occurred in children 6 and under. Of these pneumococcal-vaccine related adverse event reports to VAERS, 2,306 were deaths, with nearly 70 percent occurring in children under 6 years of age.
  • As of July 1, 2019, there have been 217 claims filed in the federal Vaccine Injury Compensation Program (VICP) for injuries and deaths following vaccination with pneumococcal conjugate vaccine (PCV), including 16 deaths and 201 serious injuries. Pneumococcal polysaccharide vaccine (PPSV23) is not covered under the federal Vaccine Injury Compensation Program (VICP) and compensation for injuries and deaths related to vaccination with PPSV23 are pursued in civil court.25

Food & Drug Administration (FDA) 

Centers for Disease Control (CDC)

Vaccine Reaction Symptoms & Ingredients

Our Ask 8, If You Vaccinate webpage contains vaccine reaction symptoms and more. 

Search for Vaccine Reactions

NVIC hosts MedAlerts, a powerful VAERS database search engine. MedAlerts examines symptoms, reactions, vaccines, dates, places, and more.

Reporting a Vaccine Reaction

Since 1982 the NVIC has operated a Vaccine Reaction Registry, which has served as a watchdog on VAERS. Reporting vaccine reactions to VAERS is the law. If your doctor will not report a reaction, you have the right to report a suspected vaccine reaction to VAERS. 

NVIC “Quick Facts” is not a substitute for becoming fully informed about pneumococcal and the pneumococcal vaccine. NVIC recommends consumers read the more complete information following the "Quick Facts", as well as the pneumococcal vaccine manufacturer product information inserts, and speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child.

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What is Pneumococcal?

Pneumococcal disease is an infection caused by Streptococcus pneumoniae (S. pneumoniae) bacteria. S. pneumoniae bacteria are gram-positive, lancet shaped, facultative anaerobic bacteria and currently over 90 known serotypes have been identified. Only a few of the serotypes cause the majority of pneumococcal infections but nearly all serotypes have the ability to cause serious disease.26

  1. pneumoniae are frequently found in the respiratory tract and up to 90 percent of healthy people may have the bacteria present in the nasopharynx (upper area of the throat behind the nose). Between 20 and 60 percent of all school children may also carry the bacteria.27 Colonization of S. pneumoniae in the nasopharynx tends to be the greatest at age 3 and declines thereafter. S. pneumoniae colonization in adults is generally acquired by exposure children, however the rates found in adults are lower than those seen in children.28

Most pneumococcal infections are mild, however, serious illness can occur.29  S. pneumoniae can cause several types of infections, including pneumonia, ear infections, sinus infections, bloodstream infections (bacteremia) and meningitis.30 Less commonly, S. pneumoniae can cause bacterial bone and joint infections,31 pericarditis, endocarditis, and peritonitis.32

In adults, pneumococcal pneumonia is the most common form of pneumococcal disease. The incubation period of pneumococcal pneumonia is between 1 and 3 days and its initial symptoms of chills, rigors, and fever often occur abruptly. Other symptoms include a productive cough, rapid heart rate and breathing, shortness of breath, poor oxygenation, rust colored sputum, weakness, and malaise. Headache, vomiting, and nausea may occur as well, although less frequently. 33

Pneumococcal bacteremia without pneumonia is another form of pneumococcal disease and symptoms include chills, fever, and a lower level of consciousness.34 An estimated 5,000 cases of pneumococcal bacteremia occur yearly in the United States.35

Pneumococcal meningitis accounts for over 50 percent of all cases of bacterial meningitis in the United States. Symptoms of meningitis may include fever, stiff neck, irritability, vomiting, seizures, headache, light sensitivity, and coma. Between 3,000 and 6,000 cases of pneumococcal meningitis occur yearly in the United States and death occurs in approximately 22 percent of adults and 8 percent of children.36

In children, acute otitis media (middle ear infection) is the most common form of pneumococcal disease and S. pneumoniae can be found in up to 55 percent of ear aspirates. Before the age of one, over 60 percent of children will have at least one middle ear infection. Otitis media results in more medical office visits than any other childhood illness.37 Symptoms of pneumococcal otitis media (middle ear infection) in children include fussiness, tugging at ears, sleeplessness, hearing difficulties, and balance issues.38 In some children, ear infections can become chronic, resulting in recurrent antibiotic use or surgery to place tubes in the ears.39 40

Lab testing of blood or other body fluids such as cerebrospinal fluid, must be completed to confirm a diagnosis of S. pneumoniae.41

Is Pneumococcal contagious?

S. pneumoniae, the bacteria which causes pneumococcal disease, is contagious and is spread through coughing, sneezing or direct contact with respiratory secretions. The exact period of communicability of pneumococcal disease is not known, however, it is generally believed that as long as the strain remains present in the respiratory secretions, it has the capacity to be transmitted to others.42 One study suggests that S. pneumoniae bacteria may exist on the surfaces of commonly handled objects for some time (minutes to no more than three days), raising the possibility of direct infection.43

Pneumococcal infections are more common during the winter and in early spring when respiratory diseases are more prevalent. Outbreaks of pneumococcal disease are not common, but the risk of an outbreak is increased in environments where a lot of people are enclosed in crowded spaces.  Environments where pneumococcal disease is more likely to spread include nursing homes, residential housing facilities, orphanages, and daycare centers.44

People, especially children, often have pneumococcal bacteria present in their nose or throat at some time or another without any clinical illness. This is referred to as “carriage.” It is still not known why carriage only rarely leads to clinical illness.45

Infection, however, occurs most often after acquiring a new pneumococcal strain, and studies have shown that 15 percent of children who acquire a new strain become ill with acute otitis media or another type of pneumococcal disease within one month of acquiring the strain.46 

What is the history of Pneumococcal in America and other countries?

Streptococcus pneumoniae was first isolated independently in 1880, both in France, by Louis Pasteur, and in the United States, by Dr. George M. Sternberg, a U.S. Army physician. 47 48 In the mid-1880s, an association between S. pneumoniae and lobar pneumonia was described in medical literature and in 1884, the discovery of the Gram Stain helped to distinguish the bacteria from other forms of pneumonia.49 50 51 During this decade, researchers also discovered that S. pneumoniae could cause meningitis.52

At the turn of the 20th century, physicians became more aware of pneumococcus, its relationship to pneumonia, and the increasing mortality rates associated with it. Published papers began to appear in medical journals detailing the impact of pneumonia in the United States. In 1900, pneumonia (and influenza) was the leading cause of infectious disease death and the third leading cause of overall death in the U.S.53 54 

Research continued and by 1909, Ludwig Handel and Franz Neufeld of the Robert Koch Institute for Infectious Diseases in Berlin, developed a technique to categorize the different strains of pneumococci.55 Between 1915 and 1945, a great deal of research focused on further understanding the structure of the S. pneumoniae bacteria, its ability to cause disease, and the impact of disease on humans. By 1940, more than 80 types of S. pneumoniae had been identified and described.56

S. pneumoniae was noted to be genetically diverse and identifiable by its unique outer capsule surrounding the bacteria. The capsule was found to be crucial in maintaining the pneumococci’s ability to cause infection by preventing other cells from devouring it, in a process known as phagocytosis. The prevalence of a particular serotype was found to be dependent on geographical location, characteristics of the infected person, and the use of antibiotics and vaccines.57 58 59

Changes in the prevalence of a particular S. pneumoniae serotype within a population were also noted to have occurred throughout its history and S. pneumoniae was determined to frequently transform through a process known as recombination, or capsular switching. 60 In this process, the bacterial cell incorporates DNA from other closely related bacteria into its own genome, enabling it to adapt, and allowing it to resist antibiotics or evade vaccines.61

As treatment of pneumococcal disease impacted the transformation of S. pneumoniae, medical interventions targeting the infection have been critical to its history. Early research into treatment options against the disease began nearly immediately after the bacteria’s identification.

One of the first antimicrobials to be studied as a possible treatment against pneumococcal disease was a quinine derivative known as optochin. Optochin, however, was found to have a narrow window of effectiveness between toxic and therapeutic doses. The development of Optochin as a potential treatment of S. pneumoniae was discontinued quickly due to the risk of toxicity.62

The next treatment of S. pneumoniae involved the use of antiserum derived first from animals (rabbits and horses) then from humans.63 During the 1930s and 40s, human antiserum was considered the primary treatment option for pneumococcal pneumonia. During this time, treatment of the individual patient evolved into a “community” responsibility, and pneumonia became one of the leading health concerns in the U.S.64

The Metropolitan Life Insurance Company, which had lost over $24 million dollars in death benefits in the wake of the 1918-1919 Spanish influenza, led as the largest campaign contributor in the fight against this respiratory disease. In 1937, it joined with the U.S. Health Service to produce a 12 minute film on pneumococcal pneumonia, which debuted at New York City’s famous Radio City Music Hall. Pneumococcal pneumonia was declared a national health emergency which required a coordinated effort between the public, physicians, and health agencies in order to advance and promote medical treatments to target the disease.

By 1940, approximately two thirds of the U.S. states and territories in would develop pneumonia-control programs and federal funding for pneumococcal increased nearly 60-fold in three years.65 In 1940, pneumonia and influenza was reported to be the fifth leading cause of infectious disease death in the U.S, and was reported to occur at a rate of 70.3 cases per 100,000 people.66

During this era, a new pneumococcal treatment option became available in the form of an antimicrobial compound known as sulfapyridine. When published research noted its ability to reduce pneumococcal disease mortality rates, it quickly became the most popular treatment option against the disease. 67 68  Its use increased even further when it was found to have successfully treated Sir Winston Churchill’s bacterial pneumonia.69

The success of sulfapyridine, and eventually penicillin, against pneumococcal pneumonia resulted in a decline in the use of human antiserum and by the late 1940s, all pneumococcal control programs had been discontinued.70 

By the mid-1940s, penicillin had become more readily available and found to be highly effective against numerous infectious diseases, including pneumococcal disease. 71 Penicillin quickly became recognized as one of the most effective treatments against S. pneumoniae associated infections.72 While several pneumococcal vaccines were developed for use between 1909 and the mid-1940s, the discovery of penicillin as an effective treatment and the preference of its use by doctors, resulted in limited use of these products. 73 74

The discovery of antimicrobials and antibiotics which were found to effectively treat a number of different infections, including S. pneumoniae, prompted a change in pneumococcal treatment protocols. The culturing and typing of infections were no longer routinely performed by clinicians, with many preferring to administer antibiotics for nearly any clinical sign of infection. Some clinicians believed that treating all infections prophylactically with antibiotics would be the safest and most effective way to prevent pneumococcal disease and others chose to prescribe antibiotics at the first sign of any illness.

By the early 1960s, pneumonia researchers, expressing concern over the indiscriminate use of antibiotic, reported that only 10 percent of all persons prescribed antibiotics actually required them. Sulfa resistant strains of S. pneumoniae had already been noted in the 1940s and by the 1960s, penicillin resistant strains had begun to emerge.75 76

Concerns over antibiotic treatment failures and death rates resulting from invasive pneumococcal disease in the 1960s prompted a renewed interest in pneumococcal vaccination development;77 however, it took researchers until the early 1980s to publish papers suggesting that the overuse of unnecessary antibiotics may be responsible for the increasing number of antibiotic-resistant strains of infection, suggesting that this practice be curtailed.78 Despite published literature, the scientific community did not sound the alarm over the rise in antibiotic resistant strains of bacteria until the mid-1990s.79 By 1998, 24 percent of pneumococcal strains were found to be resistant to penicillin and 14 percent of strains were noted to be resistant to multiple antibiotics.80

30 percent of all invasive S. pneumoniae infections are currently resistant to one or more antibiotics, with resistance noted to be dependent on geographical location.81 82 Adults over 65 and children under 5 are most likely to harbor antibiotic resistant strains of S. pneumoniae.83 

Antibiotic resistance pushed pneumococcal disease back into the public health spotlight84 85 and the need for new treatment approaches has been identified as a priority by both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC).86 87

Over 90 strains of S. pneumoniae have been identified with 10 strains found to cause approximately 62 percent of all cases of invasive pneumococcal disease globally. In the U.S., 80 percent of invasive pneumococcal disease found in children 6 and under is the result of 7 common strains.88 In 2017, there were 16,620 reported cases of invasive pneumococcal disease in the U.S and 1,220 of those cases occurred in children under 5.89

Global disease

WHO estimates S. pneumoniae to be responsible for the death of half a million children worldwide every year. 90  The majority of these deaths occur in developing countries located in Asia and sub-Saharan Africa. As with pneumococcal disease in the U.S., older adults and young children are most susceptible to infection, and only a small number of strains are responsible for the majority of infections.91

Can Pneumococcal cause injury and/or death?

Although most pneumococcal infections are mild, pneumococcal disease can cause serious illness.92 The 3 most common illnesses caused by invasive S. pneumoniae include pneumonia, meningitis, and bacteremia;93 however, S. pneumoniae can also cause other rare but serious pneumococcal infections including peritonitis, endocarditis and pericarditis, and infection of the bones and joints (septic arthritis, osteomyelitis).94

S. pneumoniae can also cause middle ear infections, conjunctivitis, and sinus infections but these infections are generally mild and rarely result in complications.95 96 S. pneumoniae can also cause a worsening of symptoms in someone with chronic bronchitis.97

The most common serious form of pneumococcal disease is pneumonia. Symptoms of infection may include rapid or difficulty breathing, chest pain, chills, fever, and cough. Older adults may also experience altered levels of alertness and confusion. Complications of pneumococcal pneumonia include pericarditis, airway obstruction, empyema, lung abscess, lung collapse, and death.98 Between 5 and 7 percent of persons with pneumococcal pneumonia die from the illness and elderly patients are most at risk of death.99

Since the introduction of pneumococcal conjugate vaccines, pneumococcal empyema, a complication of pneumococcal pneumonia which causes pus to accumulate between the lungs and the inner aspect of the chest wall, has become more common. 100 101  S. pneumoniae strains noted to cause this complication include serotype 1, 3, and 19A. 102 103

S. pneumoniae can also cause an infection of the blood, known as bacteremia. Initial symptoms of bacteremia may include a lower level of alertness, fever, and chills. Symptoms of sepsis, a serious complication of bacteremia, often include severe pain, sweaty or clammy skin, difficulty breathing, elevated heartrate, and confusion. Sepsis can lead to organ failure, tissue damage, and death.104

Pneumococcal meningitis, an infection of the lining of the spinal cord and brain, can also be cause by S. pneumoniae. Symptoms of infection often include sensitivity to light, headache, fever, neck stiffness, and confusion. In infants, symptoms may include a reduced level of alertness, lack of appetite, poor fluid intake, and vomiting.  Complications of pneumococcal meningitis include developmental delays, hearing loss, and death.105

Pneumococcal peritonitis, an infection of the lining of the walls of the abdomen and pelvis, is another rare but serious form of invasive pneumococcal disease. Pneumococcal peritonitis is more commonly found in persons with cirrhosis of the liver,106 HIV, and hepatitis C.107 but can also be the result of severe pelvic inflammatory disease, gastrointestinal ulcer or injury, or malignancy. Symptoms of infection often include diarrhea, vomiting, abdominal pain, fever, and dehydration.108

Pneumococcal endocarditis and pericarditis are 2 rare but serious heart infections. Symptoms of pneumococcal pericarditis often include fever, fatigue, chest pain which can radiate to the back, neck, abdomen or shoulder, cough, swelling of the extremities, and muffled heart sounds. Symptoms of pneumococcal endocarditis often include joint and/or muscle pain, fever, anorexia, sweating, and new or changing heart murmurs.109

In rare cases, S. pneumoniae can cause septic arthritis and osteomyelitis (bone infection). Symptoms of septic arthritis include hot, swollen, or painful joints and frequently involve the knees or ankles. Half of all persons who develop pneumococcal septic arthritis will also have osteomyelitis. Symptoms of osteomyelitis often include redness, warmth, and swelling to the infected area, fever, chills, pain, and children may show signs of lethargy or irritability.110

S. pneumoniae accounts for up to 50 percent of middle ear infections (otitis media). Symptoms of otitis media often include fever, a red or swollen ear drum, ear pain, and sleepiness. Ear and sinus infections are generally mild; however, children who develop frequent ear infections may require ear tube placement.111

Who is at highest risk for getting Pneumococcal? 

Pneumococcal disease can affect anyone; however, some people may be at a greater risk for the disease. Risk factors include age and certain pre-existing medical conditions. Approximately 90 percent of invasive pneumococcal disease occurs in adults.112 Adults considered most at risk of illness are persons 65 and older.

Persons between the age of 19 and 64 considered at highrisk of pneumococcal disease include:113

  • Smokers
  • Chronic alcoholics
  • Persons with chronic illness such as lung, heart, kidney, or liver disease
  • Individuals with asthma
  • Diabetics
  • Persons who are immunocompromised (ie HIV positive)
  • Individuals with cancer
  • Persons without a functioning spleen
  • Individuals with a cochlear implant or cerebrospinal leak
  • Persons living in a nursing home, group home, or other long-term care facility.

Adults with living with chronic diseases such as diabetes, COPD, and chronic heart disease are at risk for developing invasive pneumococcal disease at any time during the year.114

Children considered most at risk for developing invasive pneumococcal disease include young children under 2 and those who attend child care in a group setting. Additionally, Children with cochlear implants or cerebrospinal fluid leaks, chronic lung, health, kidney, or liver disease, sickle cell disease, and those with immunocompromising conditions are also consider to be at high risk for invasive disease.115

African Americans, Alaskan Natives, and certain American Native groups have been found to have higher rates of pneumococcal disease.116

Who is at highest risk for suffering complications from Pneumococcal? 

Individuals with chronic illnesses such as COPD, asthma, diabetes, and heart disease are at higher risk of acquiring pneumococcal disease and suffering from complications related to the disease. Further, inhaled medications (corticosteroids and anti-cholinergics) used to treat these medical conditions increases both the risk of invasive pneumococcal disease and the risk of complications and death from the illness.117

The risk of respiratory and cardiac complications—both of which are associated with increased mortality—is greater in individuals with chronic lung and/or heart diseases.  Additional risk factors of mortality after hospitalization for invasive pneumococcal disease include: 118

  • coexisting chronic conditions
  • re-hospitalization within 30 days of hospital discharge, and
  • Residing in a nursing home.

In adults hospitalized for invasive pneumococcal disease, risk factors for respiratory failure included: 119  

  • Age of 50 years and older
  • Chronic lung disease
  • Coronary heart disease, and
  • Infection with serotype 3, 19A or 19F.

Current smokers hospitalized with pneumococcal pneumonia have a five-fold increased risk of 30-day mortality from the disease when compared with non-smokers and ex-smokers.120

5.5 percent of non-hospitalized children will develop long-term major respiratory consequences from pneumonia of any type and the risk is 3 times higher among children hospitalized with disease.121

1 out of 100 children younger than 5 with bacteremia or sepsis (blood infection) will die from it. The risk of death from pneumococcal bacteremia is also higher among elderly people. It is estimated that 1 out of every 15 children under 5 who develop pneumococcal meningitis will die from the infection.122

Can Pneumococcal be prevented and are there treatment options?

Illnesses that can be spread by respiratory secretions can also be prevented by:123

  • Washing hands thoroughly or using hand sanitizer when handwashing is not available
  • Staying home when ill
  • Staying home when you have been exposed to illness and may be contagious
  • Using a tissue when sneezing or coughing

If invasive pneumococcal disease, such as pneumonia, meningitis or bacteremia infection is suspected, blood or cerebrospinal fluid should be collected for testing. Identification and confirmation of the specific bacteria is important as it allows clinicians to select the most appropriate antibiotic to decrease the risk of severe infection.124 Non-invasive pneumococcal pneumonia in adults can be diagnosed by a simple rapid urine test. This test can also help in the selection of antibiotics for treatment.125

Ear and sinus infections are usually diagnosed based on health history and physical examination.126 As there are multiple strains of S. pneumoniae, it is often difficult to determine which strain is responsible for a given infection, or which antibiotic will be most effective. Over-prescription of ineffective antibiotics has contributed to the growing problem of antibiotic resistance.127 128

The treatment of invasive pneumococcal infection usually begins with the use of an antibiotic that can target a number of different strains of bacteria. When lab results confirm the type of bacteria, a more selective and targeted antibiotic may be used instead.129 Oral antibiotics are prescribed for mild infections, however, more serious infections require antibiotics to be administered intravenously. In some cases, hospitalization will be required due to the severity of this illness.130 Many types of bacteria, including pneumococcal bacteria, have become resistant to antibiotics as a direct result of overuse and misuse of antibiotics.131 132

What is Pneumococcal vaccine?

NVIC strongly recommends reading the vaccine manufacturer product information insert before you or your child receives any vaccine, including pneumococcal vaccine. Product inserts are published by drug companies making vaccines and list important information about vaccine ingredients, reported health problems (adverse events) associated with the vaccine, and directions for who should and should not get the vaccine.

Links to the pneumococcal vaccine product inserts are available below or you can ask your doctor to give you a copy of the vaccine product insert to read before you or your child is vaccinated. It is best to ask your doctor for a copy of the product inserts for the vaccines you or your child is scheduled to receive well in advance of the vaccination appointment.

Pneumococcal Vaccines Licensed for Use in the U.S.

The U.S. Food and Drug Administration (FDA) and U.S. Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) has approved two different pneumococcal containing shots. There are different rules for use of these vaccines by different aged groups.

Prevnar 13 is a 13-valent pneumococcal conjugate vaccine (PCV) manufactured by Wyeth (Pfizer) pharmaceuticals, containing Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Prevnar 13 does not protect against infection and disease caused by Streptococcus pneumoniae strains not present in the vaccine.

Prevnar 13 is approved for the following uses:

  • In children between the ages of six weeks and five years of age for the prevention of invasive disease and otitis media;
  • In children and teenagers between the ages of six and seventeen years of age for the prevention of invasive disease;
  • In adults eighteen years of age and older for the prevention of pneumonia and invasive disease.

Prevnar 13 is a 13-valent Pneumococcal Conjugate Vaccine containing Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, each individually linked to non-toxic diphtheria CRM197 protein. Serotypes are each grown in a soy peptone broth and each polysaccharide is purified. Each polysaccharide is then chemically activated to make saccharide and linked to the Diphtheria CRM197 protein to form the glycoconjugate. CRM197, a nontoxic variant of diphtheria toxin, is isolated from cultures of Corynebacterium diphtheria strain C7 which has been grown in a yeast extract and casamino acids based medium or in a chemically-defined medium. CRM197 and each glycoconjugate is then purified and the individual glycoconjugates are joined to make Prevnar 13. Each 0.5ml dose of Prevnar 13 contains approximately 2.2 μg of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg of 6B saccharides, 34 μg CRM197 carrier protein, 295 μg succinate buffer, 100 μg polysorbate 80, and 125 μg aluminum as aluminum phosphate adjuvant.

PNEUMOVAX23 is a pneumococcal polysaccharide vaccine (PPSV) manufactured by Merck and contains Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A,12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F. Pneumovax 23 does not protect against infection and disease caused by Streptococcus pneumoniae strains not present in the vaccine.

PNEUMOVAX23 is approved for use in adults 50 years of age or older and in children 2 and older who are at increased risk for pneumococcal disease.

PNEUMOVAX23 is a polyvalent pneumococcal vaccine and contains a mixture of purified capsular polysaccharides comprised of Streptococcus pneumoniae types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F. PNEUMOVAX 23 is a clear, colorless and sterile solution and each 0.5-mL dose of vaccine contains 25 micrograms of each type of polysaccharide in an isotonic saline solution containing 0.25% phenol as a preservative.

What is the history of Pneumococcal vaccine use in America?

The earliest known pneumococcal vaccines in the United States date back to 1909 in the form of heat-treated, whole-cell vaccines. These early vaccines remained available for use until the mid-1930s, with several of these products containing additional vaccines aimed at preventing illnesses caused by Haemophilus influenzae, Staphylococcus aureus, Klebsiella, Neisseria catarrhalis, and more.133

The first pneumococcal vaccine trials began in South Africa in 1911 and involved miners who were administered a whole-cell vaccine consisting of the known circulating strains of pneumococcal. The results of this first study were improperly recorded and as a result, a second trial of a similarly formulated vaccine was initiated in the summer of 1912. This second vaccine was reported to offer some protection from pneumonia but this protection lasted only about 2 months. Further, while vaccination appeared to slightly reduce pneumonia rate, it had no impact on pneumonia death rates.

A third trial which involved a similar pneumococcal vaccine was reported by investigators to decrease pneumonia rates by 25 to 50 percent and death rates by 40 to 50 percent.134 Sir Almroth Knight, the primary researcher involved in the first 3 clinical trials, however, paid no attention to the strains of pneumonia used within the vaccines, making the overall effectiveness of pneumococcal vaccination difficult to determine.135

Sir F. Spencer Lister, a protégé of Sir Almroth Knight, expanded on Knight’s earlier work by developing a system to identify and type different strains of pneumococcal. Lister noted the presence of unique pneumococcal strains not found in North America and Europe.

In 1914, Lister developed the first whole-cell pneumococcal vaccine containing three specific strains of S. pneumoniae, now known as serotypes 1, 2, and 5.136 Lister’s vaccine trials involved the administration of 3 vaccine doses given 1 week apart to miners working at 3 different South African mines. All 3 mines experienced a decrease in pneumococcal morbidity and mortality in the six to twelve month period of observation post-vaccination.137

By 1918, Lister expanded on his vaccine by adding five additional pneumococcal strains and planned to administer this vaccine to all South African miners. However, by the mid- 1920s, his vaccine was found to be ineffective. By the early 1930s, pneumonia caused by strains 1, 2, 5, and 7, four strains targeted by his vaccine, remained low; however pneumonia rates from strain 3, a strain also found in his vaccine, were noted to be three times higher among those who received the vaccine.138 

During the First World War, 2 U.S. military bases began pneumococcal vaccination campaigns and troops were vaccinated with a pneumococcal vaccine containing strains 1, 2, and 3. Vaccination was found to reduce the rates of pneumonia caused by the strains specific to the vaccine but vaccine recipients were studied for a period of only 2 to 3 months and the long-term effectiveness of the vaccine was never determined.139 140

Pneumococcal vaccines were also administered in several setting during the 1918 flu pandemic, including military bases, with mixed effectiveness. Vaccines administered during this period also included strains of additional bacteria, such as B. influenza, Staphylococcus aureus, or hemolytic streptococci.141

Pneumococcal capsular polysaccharides were discovered in 1916-1917, but it took researchers until 1927 to realize that the polysaccharides could induce an immune response. The first pneumococcal polysaccharide vaccine contained pneumococcal strain 1 and strain 2, and the vaccine was administered to nearly 120,000 Civilian Conservation Corp (CCC) men in the 1930s as part of several clinical trial studies. The vaccine’s effectiveness was studies for only a few months and no long-term studies were ever completed.142 143

In 1937, a polysaccharide vaccine containing pneumococcal strain (serotype) 1 was used during a pneumonia outbreak at an adult psychiatric hospital. This trial reported that the vaccine significantly decreased pneumonia rates.144 145

Both military and civilian clinical trials of polysaccharide pneumococcal vaccines reported favorable results,146 147 and in 1947, the first pneumococcal polysaccharide vaccine licenses were granted to E.R. Squibb & Sons.148 Squibb’s adult vaccine contained serotypes 1, 2, 3, 5, 7 and 8 while its pediatric vaccine contained serotypes 1, 4, 6, 14, 18 and 19. 149

Use of these vaccines were short-lived as doctors preferred to use newly discovered antibiotics to treat pneumonia. Production of polysaccharide pneumococcal vaccines ended in 1951 and in 1954, Squibb withdrew its vaccine license due to lack of demand for the product.150 151

Pneumococcal vaccine development resumed again in 1968, this time at the insistence of National Institutes of Health (NIH) scientist Dr. Robert Austrian. Austrian had witnessed numerous antibiotic treatment failures in the clinical setting and believed pneumococcal disease rates to be much higher than reported related to a significant decrease in the use of testing to confirm a diagnosis.

Eli Lilly & Co was granted a contract by the NIH to research and develop an effective pneumococcal polysaccharide vaccine. In 1972, vaccine trials of Eli Lilly’s pneumococcal vaccine began in South Africa;152 however, by 1975, Eli Lilly had terminated its research and development after several issues with the vaccine had occurred.153 154

Meanwhile, Merck Sharp and Dohme, with knowledge and experience related to the research and development of a meningococcal polysaccharide vaccine for the United States Army in the late 1960s, had already started on a pneumococcal polysaccharide vaccine development by 1970.Merck also chose to complete pneumococcal vaccine clinical trials in South Africa and reported that their 6 and 12-valent vaccines reduced pneumococcal pneumonia disease rates by 76 and 92 percent respectively.155

Merck applied for a license to manufacture and market a 14-valent pneumococcal capsular polysaccharide vaccine, PNEUMOVAX, in 1976 and received FDA approval for the vaccine on November 21, 1977.156 In January 1978, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that the new pneumococcal vaccine be administered to all children and adults 2 and older with chronic health conditions which included sickle cell anemia, splenic dysfunction, diabetes mellitus, and chronic renal, lung, liver, and kidney disease. The vaccine was also approved for use during a pneumococcal outbreak involving a closed population, such as a nursing home or similar institution.157

Lederle, another established vaccine manufacturer, had also begun the research and development of a pneumococcal polysaccharide vaccine in the 1970s and in August 1979, PNU-IMUNE, its 14-valent pneumococcal vaccine, received FDA approval.158

By the early 1980s, pneumococcal experts recognized the need to expand the number of pneumococcal strains contained within the polysaccharide vaccine to improve coverage on a global scale. The World Health Organization (WHO) along with the governments of several countries, reported that a 23-valent pneumococcal vaccine would provide better protection against pneumococcal disease worldwide.

In 1983, both Merck and Lederle introduced pneumococcal polysaccharide vaccines (PPV23) containing 23 strains of pneumococcal which were believed to cause approximately 87 percent of all bacterial pneumonia cases in the United States. The PPV23 vaccines were reformulated to contain 25mcg of each specific antigen, a decrease from the 50mcg per antigen found in the 14-valent vaccine, in an attempt to better balance safety and immune response.159

The CDC’s Advisory Committee on Immunization Practices (ACIP) voted in 1984 to recommend that all adults 65 and older receive a dose of PPV23 vaccine. This recommendation was made despite knowing that 2 separate studies had found the vaccine to be ineffective in reducing pneumococcal infections and deaths. 160  ACIP also continued to recommend that all adults and children 2 and older with chronic illness or immunosuppression receive a dose of the vaccine.161

In 1997, PPV23 recommendations were updated to include special populations such as individuals living in nursing homes and other long-term care facilities and for use in Alaskan Natives and certain American Indians populations.162

As pneumococcal polysaccharide vaccines were found to be ineffective in children under the age of 2, vaccine development continued.163 Pneumococcal related deaths were reported to be uncommon among children except in the case of immune suppression, meningitis, or severe bacteremia following the removal of the spleen, but children 2 and under along with adults 65 and older, were still considered by health officials to be at a higher risk for pneumococcal infections.164

Development of a method to bind a polysaccharide with a carrier protein to enhance the immune response began in 1980, and in 1987, the conjugated Hib vaccine became the first vaccine using polysaccharide-protein conjugation technology to receive approval by the FDA.165

Wyeth Lederle was the first vaccine manufacturer to develop a pneumococcal conjugate vaccine. In pre-licensing clinical trials, Prevnar 7 (PCV7) was tested against an experimental meningitis C vaccine,166 which seriously compromised the scientific validity of the trial. The vaccine, however, still received approval by the FDA in February of 2000.167

The 7-valent pneumococcal conjugate vaccine contained Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM197 protein and was approved for use in infants and children at 2, 4, 6, and 12-15 months of age for the prevention of invasive disease caused by Streptococcus pneumoniae from the strains found within the vaccine.168

On June 21st, 2000, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted to recommend PCV7 vaccine for use in all children 23 months of age and younger, as well as in children ages 24 to 59 months considered to be at high-risk of serious pneumococcal infection.169

The highly successful promotion by Wyeth Lederle, the CDC, and the American Academy of Pediatrics (AAP) made Prevnar (PCV7) the best-selling new pharmaceutical product of 2000, generating $461 million in sales.170

By 2001, however, PCV7’s popularity, in conjunction with manufacturing issues, resulted in vaccine shortages. The shortages required ACIP to temporarily revise PCV7 vaccine recommendations, prioritizing the vaccine’s use in children most at risk for pneumococcal disease.171 Issues with vaccine shortages were not completely resolved until September of 2004.172

In October 2002, the FDA approved PCV7 for use in the prevention of middle ear infections (otitis media) despite clinical studies noting the vaccine to be only 7 percent effective against all types of acute otitis media.173 174

Following PCV7 introduction on a global scale, scientists began to report that while the vaccine appeared to be effective in reducing nasopharyngeal carriage of S. pneumoniae strains found within the vaccine, this reduction had resulted in a significant increase in non-vaccine type strains,175 most notably, strain 19A, a highly virulent and antibiotic-resistant serotype.176 177 In Spain, an increase in invasive pneumococcal disease occurred following the introduction of PCV7, with the emergence of several non-vaccine type strains.178 179 180

Vaccine manufacturers responded to the emergence of multiple antibiotic-resistant strains of S. pneumoniae by introducing new pneumococcal vaccines containing additional strains. In March 2009, Synflorix (PCV10), a 10-valent pneumococcal conjugate vaccine, containing three additional strains not found in PCV7 (1, 5, and 7F) received approval for use in Europe.181 One year later, in February of 2010, Wyeth pharmaceuticals received approval for Prevnar 13 (PCV13) vaccine, a 13-valent pneumococcal conjugate vaccine, which added 6 additional strains (1, 3, 5, 6A, 7F, and 19A) to the original Prevnar (PCV) vaccine.182

Recommendations for the use of PCV13 were issued promptly by the CDC’s Advisory Committee on Immunization Practices (ACIP) which essentially recommended that PCV13 be used in lieu of PCV7. Prior to FDA approval PCV13 was studied for safety in less than 4,800 healthy infants and toddlers and the vaccine was compared to infants and children receiving PCV7, alone or in combination with other vaccines.183

ACIP also recommended PCV13 for children and teenagers between 6 and 18 years of age not previously vaccinated and considered to be at high risk for pneumococcal disease related to immunosuppressive conditions including sickle cell anemia, asplenia, HIV, the presence of a cochlear implant, or cerebrospinal fluid leak.184 185 At the time of this recommendation in December of 2010, the FDA had not approved the vaccine for use in children over the age of 59 months and did not expand the usage of PCV13 vaccine for children and teenagers between the ages of 6 and 17 until January of 2013.186

In December of 2011, the FDA approved the expanded use of PCV13 under an “Accelerated Approval” process to include adults 50 years of age and older.187 The “Accelerated Approval” process allows products targeted to treat a serious condition or fill an unmet need the opportunity to receive quicker FDA approval based on laboratory tests or other measurements believed to possibly predict a clinical benefit.188

In this case, a comparison was made between antibody responses of individuals receiving either PCV13 or Merck’s 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV 13 was found to have a similar or higher antibody response when compared to PPSV23 and the FDA permitted this laboratory finding to fulfill the requirement needed to receive “Accelerated Approval”, despite knowing that the level of vaccine-induced antibodies required to protect an individual against a particular strain of pneumococcal infection is unknown.189 190

While the ACIP declined to routinely recommend PCV13 for adults over the age of 50 following the FDA’s approval to expand its usage,191 the committee did vote to recommend the vaccine for use in immunocompromised adults 19 years of age and older, in June of 2012.192 The FDA, however, did not approve PCV13 for use in adults 19 to 49 until July 11, 2016.193

In 2014, ACIP updated its recommendations for the use of PCV13, recommending the vaccine be administered to all seniors 65 and older in addition to the previously recommended PPSV23 vaccine;194 however, by October 2018, ACIP reported that is recommendation had not reduced pneumonia rates among persons 65 years and older.195

In June 2019, ACIP voted to pull back from its 2014 recommendation and stated that healthy seniors 65 and older could consider this vaccination after discussions with their physician. PCV13 is still recommended for seniors 65 years and older who have chronic health conditions and a single dose of PPSV23 is still recommended for all persons 65 and older.196

Since the introduction of PCV13, pneumococcal strains not covered within the vaccine have continued to emerge. Researchers in the United States have noted that while invasive pneumococcal disease has decreased since the introduction of pneumococcal conjugate vaccines, S. pneumoniae strains have adapted and antibiotic resistant non-vaccine strains have emerged.197 198 These non-vaccine type strains include strains 33F, 22F, 12, 15B, 15C, and 23 A.199

Korea, 200 Taiwan,201 and several Western European countries, 202 have also reported an increase in pneumococcal strains not covered by PCV13 and scientists continue to recommend pneumococcal strain monitoring and further development of vaccines in response to continued emergence of non-vaccine type strains. 203 204 205 206 207

How effective is Pneumococcal vaccine?         

PPSV23 Vaccine Effectiveness

The initial pre-licensing clinical trials of a pneumococcal capsular polysaccharide involved a comparison study of the effectiveness of a 6-valent polysaccharide vaccine against a 12-valent polysaccharide vaccine. The study involved South African gold miners between the ages of 16 and 58, a population noted to be at a higher risk for pneumococcal pneumonia. The 6-valent vaccine was reported to be 76 percent effective while the 12-valent vaccine was found to be 92 percent effective against the particular pneumococcal strains found in the vaccine.208 209

The long-term effectiveness of the vaccine was not measured as the study was limited to only one year. An additional polysaccharide vaccine effectiveness study involving both a 6-valent and 13-valent polysaccharide vaccine found a 79 percent reduction in pneumococcal pneumonia and an 82 percent reduction in pneumococcal bacteremia caused by the strains found in the vaccine.210

In the United States, two post-licensing trials on the effectiveness of the original 14-valent pneumococcal polysaccharide vaccine in the elderly or persons with chronic medical conditions found the vaccine to be ineffective against bronchitis and pneumonia in this particular population.211 212 213

Additional research on the effectiveness of the pneumococcal polysaccharide vaccine based on the CDC’s pneumococcal surveillance system found the vaccine to be 57 percent effective against the serotypes found within PNEUMOVAX23 (PPSV23) in persons 6 and older, between 65 and 84 percent effective in persons with chronic illness (ie diabetes, congestive heart failure, COPD, etc), and 75 percent effective in healthy persons 65 and older. Vaccine effectiveness, however, could not be determined in certain populations of individuals with immunosuppressive conditions.214

When PNEUMOVAX23 (PPSV23) was administered in combination with ZOSTAVAX, Merck’s live attenuated shingles vaccine, shingles antibody levels were found to be significantly lower when compared to administering the shingles vaccine four weeks after PNEUMOVAX23 administration.215

A 2008 study found that while PPSV23 reduced the risk of invasive pneumococcal disease in the elderly by 38 percent, it had no impact on pneumonia rates.216 In 2010, researchers found the vaccine to be completely ineffective at reducing the rates of hospitalization or death in persons previously treated for community acquired pneumonia.217 The vaccine was also found to be ineffective in both transplant patients,218 and persons with HIV who had low CD4+ cell counts219 and did not reduce the rates of pneumonia in persons with rheumatoid arthritis.220

PCV 13 Vaccine Effectiveness

Information on pneumococcal conjugate vaccine efficacy found in the Prevnar 13(PCV13) product insert reports information pertaining to the original PCV vaccine, Prevnar (PCV7). PCV7 was reported to be 100 percent effective at preventing invasive disease caused by S. pneumoniae during the pre-licensing clinical trial which took place over a 34 month period. An eight month extended follow-up of vaccine recipients reported the vaccine’s efficacy to be between 93 and 97.4 percent effective.221

In clinical studies pertaining to the PCV vaccine for the prevention of acute otitis media, studies found PCV7 to be only 7 percent effective at preventing acute otitis media and children who received PCV7 were noted to be at a higher risk for developing acute otitis media from strains not covered by the vaccine. Studies also found that PCV7 reduced the need for tympanostomy tubes (ear tubes) by only about 20 percent.222

One large scale study involving nearly 85,000 adults 65 and older found PCV13 to be 45.6 percent effective against vaccine-type pneumococcal pneumonia, 45 percent effective against vaccine-type non-bacteremic pneumococcal pneumonia and 75 percent effective against all vaccine-type invasive pneumococcal disease.223

The Prevnar 13(PCV13) product insert also states that effectiveness of the vaccine cannot be established in the following population:224

  • Infants born prematurely
  • Persons with HIV-infection
  • Children with sickle cell disease
  • Persons who had received an allogeneic hematopoietic stem cell transplant

Following FDA approval of the first pneumococcal conjugate vaccine, Prevnar (PCV7), researchers discovered that while the vaccine was effective in reducing the risk of infection caused by the 7 strains found within the vaccine, strains not found within the vaccine began to increase. Most notably, strain 19A, a highly virulent strain resistant to all antibiotics FDA approved for use in children for the treatment of acute otitis media, emerged.225 226

In addition to pneumococcal strain replacement, the introduction of PCV7 resulted in a significant increase in pneumococcal empyema, a complication of pneumococcal pneumonia resulting in an accumulation of pus between the lungs and the inner aspect of the chest wall.227 228 The most common strains causing empyema were found to be pneumococcal strains 1, 3 and 19A, three strains not covered in the PCV7 vaccine.229 230

While invasive disease from vaccine-type strains decreased significantly within the first four years following the introduction of PCV7, antibiotic resistant non-vaccine type strains began to take their place.231 In one particular population of Alaska Native children, the introduction of the PCV7 vaccine caused a 140 percent increase of invasive pneumococcal disease from strains not found in the vaccine.232

Rates of pneumococcal meningitis by antibiotic resistant strains not found in the PCV7 vaccine continued to increase, which prompted researchers to emphasize the need for better pneumococcal vaccines.233

The 2010 introduction of PCV13 vaccine, adding six additional strains to the original PCV7, resulted in a further decline of invasive pneumococcal disease. However, PCV 13 vaccine has not been completely effective in eliminating vaccine-strain invasive pneumococcal disease and serious infections have persisted despite the licensing of a broader targeting vaccine.234 235 236 237

In addition to the vaccine’s ineffectiveness in eliminating pneumococcal disease from all strains contained within the vaccine, non-vaccine type strains have also emerged in the United States, most notably strains 33F, 22F, 12, 15B, 15C, and 23 A.238 Other countries have experienced a similar situation, including Taiwan, which noted a decrease in vaccine-type strain invasive disease and confirmed pneumococcal disease but an increase in non-vaccine type strain invasive disease, most notably caused by strains 23A, 15A and 15B.239

Korea has also reported high rates of antibiotic-resistant strains not found in PCV13 since the introduction of the vaccine.240 Non-vaccine type strains continue to appear in many Western European countries, prompting researchers stress the need for new vaccines to cover the antibiotic-resistant strains of S. pneumoniae not found within the current vaccines.241 242 243

Researchers in the United States have noted that while invasive pneumococcal disease has decreased since the introduction of pneumococcal conjugate vaccines, S. pneumoniae strains have continued to adapt and this has resulted in the ongoing emergence of antibiotic resistant non-vaccine serotypes.244 245

The use of pneumococcal conjugate vaccines has also caused an increase in other serious pathogens such as Haemophilus influenzae and Moraxella catarrhalis. Since the introduction of PCV vaccines, H. influenzae and M. catarrhalis otitis media have increased to replace S.pneumoniae otitis media.246

While the CDC and other global health organizations have attributed the decrease in invasive pneumococcal disease to vaccination, the introduction of pneumococcal conjugate vaccines has brought changes to clinical practice. Emergency room collection of blood cultures, once a routine practice in the assessment and treatment of children presenting with fever in the emergency room, have decreased since PCV vaccine introduction. 247 This change in clinical treatment protocol may be artificially inflating the rate of decrease of pneumococcal disease in children and reducing the detection of non-vaccine type replacement strains.248

A study of Aboriginals living in Western Australia found that while PCV7 vaccination decreased the number of vaccine-type invasive pneumococcal infections in the elderly and young children, it significantly increased the amount of non-vaccine type pneumococcal diseases in adults.249

Another study involving a similar population in Australia found that vaccine strains of pneumococcal were not replaced by non-vaccine strain infections in children but non-vaccine strain infections rose significantly in adults. This offset any potential benefit that vaccination might have had on the adult population.250

At the CDC’s October 2018 ACIP meeting, public health officials that vaccinating all persons 65 and older with PCV13 has had no impact on reducing the rates of both invasive and non-invasive pneumococcal disease.251 In June 2019, ACIP voted to pull back from its 2014 recommendation and stated that healthy seniors 65 and older could consider this vaccination after discussions with their physician. PCV13 is still recommended for seniors 65 years and older who have chronic health conditions and a single dose of PPSV23 is still recommended for all persons 65 and older.252

The continued emergence of non-vaccine type pneumococcal strains has resulted in the development of new pneumococcal vaccines. Merck is currently in stage 3 clinical trials of a 15-valent pneumococcal conjugate vaccine, which will add strain 22F and 33F to the 13 strains currently found in PCV13.253 

Pfizer was recently awarded Breakthrough Therapy Designation by the FDA for a new 20-valent pneumococcal vaccine.254  Breakthrough Therapy Designation allows drug companies the opportunity “to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).”255

Can Pneumococcal vaccine cause injury and death?

According to the CDC, problems that may result following vaccination with PCV13, PPSV23, and any other vaccine include:256 257

  • Severe allergic reactions occurring within a few minutes or a few hours of vaccination
  • Severe shoulder pain limiting the movement in the arm where administration occurred.
  • Fainting or collapse following vaccination. It may be advised to sit or lie down for approximately 15 minutes following vaccination to prevent fainting and injuries that could result from a fall. It is important to notify your health care provider if you have ringing in the ears, visual changes, or dizziness following vaccination.

PCV13 vaccine side-effects (Pneumococcal Conjugate Vaccine)

Adverse reactions following administration of PCV13 differed by dose in the series and age of the recipient. In children, the most commonly reported reactions included irritability, drowsiness, loss of appetite, redness, pain, or swelling to the vaccine site, and mild or moderate fever.

Children who received PCV13 at the same time as the inactivated influenza vaccine were noted to be at a higher risk for febrile seizures.

In adults, injection site redness, swelling, and pain, fatigue, fever, chills, headache, and muscle pain were most commonly reported.258

Prevnar 13 (PCV13) adverse reactions reported in infants and young children during pre-licensing clinical trials: injection site pain, swelling, redness, fever, decreased appetite, increased and decreased sleep, irritability, diarrhea, vomiting, rash, hives, hypersensitivity reaction including bronchospasm, facial swelling, and shortness of breath, seizures, pneumonia, gastroenteritis, bronchiolitis, and death (reported as SIDS).259

Prevnar 13 (PCV13) adverse reactions reported in adults during pre-licensing clinical trials: Injection site pain, swelling, and redness, limited arm movement, fever, vomiting, chills, muscle pain, fatigue, headache, decreased appetite, rash, joint pain, and death (deaths reported in the pre-licensing clinical trials included deaths from cancer, cardiac disorders, peritonitis, Mycobacterium avium complex pulmonary infection, and septic shock.)260

Prevnar 13 (PCV13) adverse reactions reported post-marketing: Cyanosis, lymphadenopathy at the injection site, anaphylaxis, shock, hypotonia, pallor, apnea, angioneurotic edema, erythema multiforme, injection site itching, hives, and rash.261

Pre-licensing clinical trials of the first pneumococcal conjugate vaccine, Prevnar (PCV7), compared the safety of Prevnar (PCV7) against an experimental meningitis C vaccine, seriously compromising the scientific validity of the trial.

In pre-licensing clinical trials of Prevnar (PCV7), children in groups who received the pneumococcal vaccine suffered more seizures, irritability, high fevers and other reactions. There were 12 deaths in the Prevnar (PCV7) group, including 5 Sudden Infant Death Syndrome (SIDS) deaths. No long term studies were completed to evaluate whether Prevnar (PCV7) vaccine given alone or in combination with other vaccines had any association with chronic illness or disabilities, such as the development of diabetes, asthma, seizure disorders, learning disabilities, ADHD, or autism.262

Pre-licensing clinical safety trials of Prevnar 13 (PCV13) compared this next generation vaccine against the original Prevnar (PCV7) vaccine, a vaccine inadequately studied for safety and by 2012, concerns regarding a link between febrile seizure and Prevnar 13(PCV13) had been reported.263 264

PCV13 was found to be associated with an elevated risk of febrile seizures when administered independently265 as well as when given in combination with the inactivated injected influenza vaccine (IIV). 266 The CDC continues to encourage simultaneous vaccine of both PCV13 and IIV vaccines despite knowledge of an increased risk of seizures in children.267

Studies have also linked PCV vaccine to Guillain-Barre Syndrome,268 polyserositis,269 septic shoulder270 and erythema multiforme.271

PPSV23 vaccine side-effects (Pneumococcal Polysaccharide)

According to the CDC, approximately 50 percent of individuals who receive the pneumococcal polysaccharide vaccine (PPSV23) experience pain and redness at the injection site. Muscles aches, fever, and more severe localized reactions can also occur following administration of PPSV23.272

PNEUMOVAX23 (PPSV23) adverse reactions reported in adults during pre-licensing clinical trials: injection site pain, redness, itching, bruising and swelling, headache, chills, fever, diarrhea, dyspepsia, nausea, upper respiratory infection, back pain, neck pain, pharyngitis, muscle pain, fatigue, depression, ulcerative colitis, chest pain, angina pectoris, heart failure, tremor, stiffness, sweating, stroke, lumbar radiculopathy, pancreatitis, myocardial infarction, and death.273

Nearly 80 percent of individuals participating in pre-licensing clinical trials experienced an injection-site adverse reaction following revaccination at three to five years following the initial vaccine. The rate of systemic adverse reactions (headache, fatigue, myalgia) following revaccination with PPSV23 was also higher with 33 percent of adults aged 65 and older and 37.5 percent of adults between 50 and 64 reporting an adverse reaction.274

PNEUMOVAX23 (PPSV23) adverse reactions reported post-marketing: Anaphylactoid reactions, serum sickness, angioneurotic edema, arthritis, arthralgia, vomiting, nausea, decreased limb mobility, peripheral edema in the limb where injection occurred, fever, malaise, cellulitis, injection site warmth, lymphadenopathy, lymphadenitis, leukocytosis, thrombocytopenia in patients with stabilized idiopathic thrombocytopenic purpura, hemolytic anemia in patients who have had other hematologic disorders, paresthesia, Guillain-Barré syndrome, radiculoneuropathy, febrile convulsion, rash, erythema multiforme, urticaria, and cellulitis-like reactions.275

While PNEUMOVAX23 (PPSV23) is approved for use in children aged two and older with conditions such as chronic heart and lung disease, diabetes, cochlear implants, cerebrospinal fluid leaks, sickle cell anemia, functional or anatomic asplenia, and immunosuppression, no information on vaccine safety or effectiveness in children is available from the vaccine’s product insert.276

Studies have linked PPSV23 to systemic inflammatory reactions,277 cellulitis and fever.278 279 280 281 282

As of May 31, 2019, there have been 21,536 serious adverse events reported to the Vaccine Adverse Events Reporting System (VAERS) in connection with pneumococcal vaccinations (PCV7, PCV13, PPSV23). Over 60 percent of these reported serious pneumococcal vaccine-related adverse events occurred in children 6 and under. Of these pneumococcal-vaccine related adverse event reports to VAERS, 2,306 were deaths, with nearly 70 percent occurring in children under 6 years of age.  However, the numbers of vaccine-related injuries and deaths reported to VAERS may not reflect the true number of serious health problems that occur after pneumococcal vaccination.

Even though the National Childhood Vaccine Injury Act of 1986 legally required pediatricians and other vaccine providers to report serious health problems following vaccination to federal health agencies (VAERS), many doctors and other medical workers giving vaccines to children and adults fail to report vaccine-related health problem to VAERS. There is evidence that only between 1 and 10 percent of serious health problems that occur after use of prescription drugs or vaccines in the U.S. are ever reported to federal health officials who are responsible for regulating the safety of drugs and vaccines and issue national vaccine policy recommendations.283 284 285 286 287

As of July 1, 2019, there have been 217 claims filed in the federal Vaccine Injury Compensation Program (VICP) for injuries and deaths following vaccination with pneumococcal conjugate vaccine (PCV), including 16 deaths and 201 serious injuries. Of that number, the U.S. Court of Claims administering the VICP has compensated 56 children and adults, who have filed claims for pneumococcal conjugate vaccine injury.288 Pneumococcal polysaccharide vaccine (PPSV23) is not covered under the federal Vaccine Injury Compensation Program (VICP) and compensation for injuries and deaths related to vaccination with PPSV23 are pursued in civil court.289

Who is at highest risk for complications from Pneumococcal vaccine?

There is a gap in medical knowledge in terms of doctors being able to predict who will have an adverse reaction to pneumococcal vaccination, and who will not.

Children receiving multiple vaccines simultaneously may be more at risk for developing complications as studies have found that children receiving the pneumococcal conjugate vaccine (PCV13) at the same time as the trivalent inactivated influenza vaccine (IIV) were nearly six-times more likely to develop febrile seizures.290 291

Healthy adults receiving a second dose of pneumococcal polysaccharide vaccine (PPSV23) within a few years of a first dose may also be at higher risk of complications as revaccination has been noted to be associated with more frequent and severe localized injection site reactions. 292

Who should not get Pneumococcal vaccine?

According to the CDC, certain persons should not get PCV13 (pneumococcal conjugate vaccine), or should postpone getting it. These persons include:293

  • Anyone who has had a life-threatening allergic reaction to: a previous dose of PCV13; a diphtheria toxoid containing vaccine (IE DTaP vaccine); or previous dose of PCV7 vaccine, an earlier version of pneumococcal conjugate vaccine, should not get PCV13.
  • Anyone with a severe allergy to any ingredient found in PCV13 should not receive the vaccine. It is important to tell your doctor about any severe allergies that you or the person receiving the vaccine may have.
  • If you or your child are not feeling well, a discussion with your health care provider about delaying PCV13 vaccination should be considered.

Persons who should not get PPSV23 (pneumococcal polysaccharide vaccine), or should postpone getting the vaccine include:294

  • Anyone who has had a life-threatening allergic reaction to a previous dose of PPSV23 should not get another dose
  • Anyone with a severe allergy to any ingredient found in PPSV23 should not receive the vaccine. It is important to tell your doctor about any severe allergies.
  • Pregnant women should not receive this vaccine
  • Children under the age of two should not receive this vaccine
  • Persons who are moderately or severely ill should wait until they have recovered fully before receiving this vaccine.

Prevnar 13 (PCV13)

Contraindications to receiving the Prevnar 13 (PCV13) vaccine documented in Wyeth Pharmaceuticals product insert include persons who have experienced a severe allergic reaction or anaphylaxis to any component of Prevnar 13 (PCV13) or any vaccine containing diphtheria toxoid.

The Prevnar 13 (PCV13) package insert warns that apnea following administration with Prevnar 13 (PCV13) has occurred in infants born prematurely. The infant’s medical status as well as the possible risks and potential benefits to vaccination should be carefully evaluated prior to considering Prevnar 13 (PCV13).

Persons with altered immune systems may have a reduced response to vaccination with Prevnar 13 (PCV13). Data on the administration of Prevnar 13 (PCV13) to women who are pregnant is insufficient for Wyeth pharmaceuticals to provide any information on the risks of vaccination during pregnancy.

There is no available data on the effects of Prevnar 13 (PCV13) on the breast-fed infant and it is recommended that breastfeeding women carefully consider the possible risk of vaccination on the infant when considering this vaccine.

Prevnar 13 (PCV13) has not been studied for its potential to cause cancer, genetic mutations or male infertility. Studies on female fertility were limited to the vaccine’s effects on female rabbits. 295

PNEUMOVAX23 (PPSV23)                

Contraindications to receiving the PNEUMOVAX23 (PPSV23) vaccine documented in Merck’s product insert include persons who have experienced a severe allergic reaction or anaphylaxis to any component of PNEUMOVAX23 (PPSV23).

PNEUMOVAX23 (PPSV23) should not be administered to children under the age of two and Merck warns that vaccination with PNEUMOVAX23 (PPSV23) should be deferred in individuals who are moderately or severely ill.

Caution is advised when vaccinating any person with a severely compromised pulmonary and/or cardiovascular function where a reaction may cause a significant health risk.

PNEUMOVAX23 (PPSV23) may not be effective for the prevention of pneumococcal meningitis persons who have cerebrospinal fluid leaks and persons with altered immune status may not respond effectively to vaccination.

PNEUMOVAX23 (PPSV23) is a Pregnancy Category C product and it is not known whether the vaccine can cause fetal harm or affect reproduction. It is also unknown whether PNEUMOVAX23 is found in human milk and as a result, Merck cautions the use of PNEUMOVAX23 in both pregnant and breastfeeding women.296

NVIC Note: Some doctors only vaccinate children who are healthy and are not sick at the time of vaccination with a coinciding viral or bacterial infection. If you do not want your acutely ill child vaccinated and your doctor disagrees with you, you may want to consider consulting one or more other trusted health care professionals before vaccinating.

What questions should I ask my doctor about the Pneumococcal vaccine?

NVIC’s If You Vaccinate, Ask 8! Webpage downloadable brochure suggests asking eight questions before you make a vaccination decision for yourself, or for your child. If you review these questions before your appointment, you will be better prepared to ask your doctor questions.  Also make sure that the nurse or doctor gives you the relevant Vaccine Information Statement (VIS) for the vaccine or vaccines you are considering well ahead of time to allow you to review it before you or your child gets vaccinated. Copies of VIS for each vaccine are also available on the CDC's website and there is a link to the VIS for vaccines on NVIC's “Quick Facts” at the top of this page.

It is also a good idea to read the vaccine manufacturer product insert that can be obtained from your doctor or public health clinic because federal law requires drug companies marketing vaccines to include certain kinds of vaccine benefit, risk and use information in product information inserts that may not be available in other published information. Wyeth Pharmaceutical Prevnar 13 and Merck’s PNEUMOVAX23 vaccine product inserts are located on the Food and Drug Administration’s website.

Other questions that may be useful to discuss with your doctor before getting the pneumococcal vaccine are: 

  • If other vaccines in addition to pneumococcal vaccine are scheduled for my child at this office visit, am I allowed to modify the schedule so fewer vaccines are given at once?
  • What should I do if my child has a high fever or appears very ill after vaccination?
  • What other kinds of reaction symptoms should I call to report after pneumococcal vaccination?
  • If the pneumococcal vaccine doesn’t protect my child, do I have any other options for preventing pneumococcal infection?

Under the National Childhood Vaccine Injury Act of 1986, doctors and all vaccine providers are legally required to give you vaccine benefit and risk information before vaccination; record serious health problems following vaccination in the permanent medical record; keep a permanent record of all vaccines given, including the manufacturer’s name and lot number; and report serious health problems, injuries and deaths that follow vaccination to VAERS.

Remember, if you choose to vaccinate, always keep a written record of exactly which shots/vaccines you or your child have received, including the manufacturer’s name and vaccine lot number. Write down and describe in detail any serious health problems that develop after vaccination, and keep vaccination records in a file you can access easily.  

It also is important to be able to recognize a vaccine reaction and seek immediate medical attention if the reaction appears serious, as well as know how to make a vaccine reaction report to federal health officials at the Vaccine Adverse Reporting System (VAERS). NVIC’s Report  Vaccine Reactions—It’s the Law webpage can help you file a vaccine reaction report yourself to VAERS if your doctor fails or refuses to make a report.

NVIC Press Releases, Statements & Commentaries Related to Pneumococcal

The Vaccine Reaction

Additional Bibliography of References

Manufacturer Product Information Inserts:

World Health Organization

Selected Media Articles

Medical Literature

References

1 CDC Pneumococcal Disease – Types of Infection. Sept. 6, 2017

2 CDC Pneumococcal Disease For Clinicians - Streptococcus pneumoniae. Sept. 6, 2017

3 CDC Pneumococcal Disease: Symptoms and Complications. Sept 6, 2017

4 Ibid

5 CDC Pneumococcal Disease For Clinicians – Transmission. Sept 6, 2017

6 CDC Pneumococcal Disease For Clinicians – Risk Factors. Sept. 6, 2017

7 CDC Pneumococcal Disease – Clinical Features. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

8 World Health Organization (WHO) Pneumonia. Nov. 7, 2016

9 CDC. Table 20. Leading causes of death and numbers of deaths, by age: United States, 1980 and 2016. 2017

10 CDC National Notifiable Infectious Diseases and Conditions: United States – TABLE 2h. Reported cases of notifiable diseases, by region and reporting area - - United States and U.S. territories, 2017 Atlanta, GA. CDC Division of Health Informatics and Surveillance, 2018.

11 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent Package Insert Dec. 30, 2014

12 FDA Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Package Insert Aug. 22, 2017

13 CDC Prevention of Pneumococcal Disease Among Infants and Children --- Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Dec. 10, 2010; 59(RR11);1-18

14 CDC Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Children Aged 6–18 Years with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR June 28, 2013; 62(25);521-524

15 CDC Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Oct. 12, 2012; 61(40);816-819

16 Crawford, C ACIP Approves New Guidance on HPV, Pneumococcal Vaccines AAFP Jul. 3, 2019

17 CDC Pneumococcal Disease – Pneumococcal Vaccines. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

18 Eskola J, Kilpi T, Palmu A et al.Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001 Feb 8;344(6):403-9.

19 Dagan R. The potential effect of widespread use of pneumococcal conjugate vaccines on the practice of pediatric otolaryngology: the case of acute otitis media. Curr Opin Otolaryngol Head Neck Surg. 2004 Dec;12(6):488-94.

20 CDC Licensure of a 13-Valent Pneumococcal Conjugate Vaccine (PCV13) and Recommendations for Use Among Children --- Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Mar. 12, 2010; 59(09);258-261

21 Bergenfelz C, Hakansson AP Streptococcus pneumoniae Otitis Media Pathogenesis and How It Informs Our Understanding of Vaccine Strategies. Curr Otorhinolaryngol Rep. 2017; 5(2): 115–124.

22 Lee GM Pneumococcal Vaccines CDC – ACIP Presentation Feb. 28, 2019

23 FDA Prevnar 13 Package Insert Aug. 22, 2017

24 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent Package Insert Dec. 30, 2014

25 Health Resources & Services Administration (HRSA) Covered Vaccines. June 2019

26 CDC Pneumococcal Disease – Streptococcus pneumoniae Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

27 CDC Pneumococcal Disease For Clinicians – Streptococcus pneumoniae. Sept. 6, 2017

28 Isturiz R, Sings HL, Hilton B et al. Streptococcus pneumoniae serotype 19A: worldwide epidemiology. Expert Rev Vaccines. 2017 Oct;16(10):1007-1027

29 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

30 CDC Pneumococcal Disease – Types of Infections. Sept. 6, 2017

31 Tan TQ.  Pediatric Invasive Pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate VaccinesClinical Microbiology Reviews.  2012 July; 25(3): 409-419.

32 Neives Prado CA Pneumococcal Infections (Streptococcus pneumoniae) Clinical Presentation. Medscape. Aug 27, 2018

33 CDC Pneumococcal Disease – Clinical Features. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

34 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

35 CDC Pneumococcal Disease For Clinicians – Clinical Features. Sept. 6, 2017

36 CDC Pneumococcal Disease – Clinical Features. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

37 Ibid

38 MedlinePlus Ear Infections. Oct. 1, 2018

39 CDC.  Ear Infections Dec. 7, 2017

40 World Health Organization. Pneumococcal vaccines WHO position paper - 2012. Weekly epidemiological record Apr 6, 2012; 14(87); 129-144.

41 CDC Pneumococcal Disease – Laboratory Diagnosis. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

42 CDC Pneumococcal Disease For Clinicians – Transmission. Sept. 6, 2017

43 Marksa LR, Reddingera RM, Hakansson AP.  Biofilm Formation Enhances Fomite Survival of Streptococcus pneumoniae and Streptococcus pyogenes
Infect. Immun. 2014;82(3): 141-1146.

44 World Health Organization. Pneumococcal vaccines WHO position paper - 2012. Weekly epidemiological record Apr 6, 2012; 14(87); 129-144.

45 CDC Pneumococcal Disease Risk Factors and Transmission Nov. 7, 2017

46 Tan TQ.  Pediatric Invasive Pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate Vaccines.  Clin Microbiol Rev.  2012 July; 25(3): 409-419.

47 Watson DA, Musher DM, Jacobson JW, et al. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis. 1993 Nov;17(5):913-24.

48 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

49 Bartholomew JW, Mittwer T, THE GRAM STAIN Bacteriol Rev. 1952 Mar; 16(1): 1–29.

50 CDC Pneumococcal Disease  Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

51 Watson DA, Musher DM, Jacobson JW, et al. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis. 1993 Nov; 17(5):913-24.

52 Ibid

53 Centers for Disease Control and Prevention, National Center for Health Statistics. Leading Causes of Death, 1900-1998.  Accessed online Oct. 21, 2018

54 Chow S.  Pneumonia History. News Medical Lifesciences Oct 11, 2015.

55 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

56 CDC Pneumococcal Disease  Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

57 Kalin M, Pneumococcal serotypes and their clinical relevance. Thorax 1998; 53(3):159-162.

58 Hausdorff WP, Siber G, Paradiso PR.  Geographical differences in invasive pneumococcal disease rates and serotype frequency in young children. Lancet.  March 24, 2001(357):  950-952.

59 Tan TQ.  Pediatric Invasive pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate VaccinesClin Microbiol Rev. 2012; 25(3): 409-419.

60 Wyres KL, Lambertsen LM, Croucher NJ, et al. Pneumococcal Capsular Switching:  A Historical Perspective. J. Infect. Dis. 2013; 207(3): 439-449.

61 Mostowy R, Croucher NJ, Hanage WP, et al. Heterogeneity in the Frequency and Characteristics of Homologous Recombination in Pneumococcal Evolution. PloS Genetics May 1, 2014.

62 Watson DA, Musher DM, Jacobson JW, et al. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis. 1993 Nov;17(5):913-24.

63 Ibid

64 Podolsky SH.  The Changing Fate of Pneumonia as a Public Health Concern in 20th-Century America and BeyondAm J Public Health. 2005 December; 95(12): 2144–2154.

65 Ibid

66 Centers for Disease Control and Prevention, National Center for Health Statistics. Leading Causes of Death, 1900-1998.  Accessed online Oct. 21, 2018

67 Watson DA, Musher DM, Jacobson JW, et al. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis. 1993

68 Whitby LEH, CHEMOTHERAPY OF PNEUMOCOCCAL AND OTHER INFECTIONS: WITH 2-(p-AMINOBENZENESULPHONAMIDO) PYRIDINE. Lancet 1938 May 28; 231(5987): 1210-1212

69 Chow S.  Pneumonia History. News Medical Oct 11, 2015.

70 Podolsky SH.  The Changing Fate of Pneumonia as a Public Health Concern in 20th-Century America and BeyondAm J Public Health. 2005 December; 95(12): 2144-2154.

71 Watson DA, Musher DM, Jacobson JW, et al. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis. 1993

72 CDC Pneumococcal Disease Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

73 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

74 CDC Pneumococcal Disease Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

75 Podolsky SH.  The Changing Fate of Pneumonia as a Public Health Concern in 20th-Century America and BeyondAm J Public Health. 2005 December; 95(12): 2144-2154.

76 Lobanovska M, Pilla G Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future? Yale J Biol Med. 2017 Mar 29; 90(1):135-145.

77 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

78 Podolsky SH.  The Changing Fate of Pneumonia as a Public Health Concern in 20th-Century America and BeyondAm J Public Health. 2005 December; 95(12): 2144-2154.

79 Ibid

80 Whitney CG, Farley MM, Hadler J et al Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000 Dec 28;343(26):1917-24.

81 CDC. Pneumococcal Disease: Drug Resistance.  Sep. 6, 2017

82 CDC ANTIBIOTIC RESISTANCE THREATS in the United States, 2013. – Drug Resistant Streptococcus Pneumoniae 2013. Page 79.

83 Kyaw, MH, Lynfield, R, Schaffner, W, Craig AS, Hadler J, Reingold A, et al. Effect of Introduction of the Pneumococcal Conjugate Vaccine on Drug-Resistant Streptococcus pneumoniae.  N Engl J Med April 6, 2006; 354: 1455-1463.

84 CDC. Pneumococcal Disease: Drug Resistance.  Jan 30, 2018

85 Podolsky SH.  The Changing Fate of Pneumonia as a Public Health Concern in 20th-Century America and Beyond.  Am J Public Health. 2005; 95(12): 2144-2154.

86 CDC ANTIBIOTIC RESISTANCE THREATS in the United States, 2013. – Drug Resistant Streptococcus Pneumoniae 2013. Page 79.

87 World Health Organization.  Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics 2017.  Feb. 25, 2017

88 CDC Pneumococcal Disease – Streptococcus pneumoniae Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

89 CDC National Notifiable Infectious Diseases and Conditions: United States – TABLE 2h. Reported cases of notifiable diseases, by region and reporting area - - United States and U.S. territories, 2017 Atlanta, GA. CDC Division of Health Informatics and Surveillance, 2018.

90 CDC Global Pneumococcal Disease and Vaccine. Sep. 6, 2017

91 WHO Immunization, Vaccines and Biologicals - Pneumococcal disease. Sep. 29, 2014

92 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

93 Ibid

94 Neives Prado CA Pneumococcal Infections (Streptococcus pneumoniae) Clinical Presentation. Medscape. Aug 27, 2018

95 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

96 Neives Prado CA Pneumococcal Infections (Streptococcus pneumoniae) Clinical Presentation. Medscape. Aug 27, 2018

97 Ibid

98 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

99 Ibid

100Fletcher, MA, Schmitt HJ, Syrochkina M et al. Pneumococcal empyema and complicated pneumonias: global trends in incidence, prevalence, and serotype epidemiology. Eur J Clin Microbiol Infect Dis. 2014; 33(6): 879–910.

101 Burgos J1, Lujan M, Falcó V, et al. The spectrum of pneumococcal empyema in adults in the early 21st century. Clin Infect Dis. 2011 Aug 1;53(3):254-61

102 Shen CF, Wang SM, Lee KH et al. Childhood invasive pneumococcal disease caused by non-7-valent pneumococcal vaccine (PCV7) serotypes under partial immunization in Taiwan. J Formos Med Assoc. 2013 Sep;112(9):561-8

103 Byington CL, Korgenski K, Daly J et al. Impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema. Pediatr Infect Dis J. 2006 Mar;25(3):250-4.

104 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

105 Ibid

106 Capdevila O, Pallares R, Grau I et al. Pneumococcal peritonitis in adult patients: report of 64 cases with special reference to emergence of antibiotic resistance. Arch Intern Med. 2001 Jul 23; 161(14):1742-8.

107 Waisman DC, Gregory J Tyrrell GJ, Kellner JD et al. Pneumococcal peritonitis: Still with us and likely to increase in importance. Can J Infect Dis Med Microbiol. 2010 Spring; 21(1): e23–e27.

108 Neives Prado CA Pneumococcal Infections (Streptococcus pneumoniae) Clinical Presentation. Medscape. Aug 27, 2018

109 Ibid

110 Ibid

111 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

112 CDC Pneumococcal Disease – Fast Facts. Jan. 23, 2018

113 CDC Pneumococcal Disease – Risk Factors and Transmission. Nov 7, 2017

114 Torres A, Blasi F, Dartois N, Akova M.  Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease. Thorax.  2015; 70: 984-989.

115 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

116 CDC Pneumococcal Disease For Clinicians – Risk Factors. Sept. 6, 2017

117 Torres A, Blasi F, Dartois N, Akova M.  Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal diseaseThorax.  2015; 70: 984-989.

118 Ibid

119 Ibid

120 Ibid

121 Edmond K, Scott S, Korczak V, Ward C, Sanderson C, Theodoratou E, Clark A, Griffiths U, Rudan I and Campbell H.  Long Term Sequelae from Childhood Pneumonia; Systematic Review and Meta-AnalysisPloS One. 2012: 7(2): e31239

122 CDC Pneumococcal Disease - Symptoms and Complications. Sep. 6, 2017

123 CDC Personal NPIs: Everyday Preventive Actions. Aug. 2, 2017

124 CDC Pneumococcal Disease - Diagnosis and Treatment. Sept. 6, 2017

125 CDC Pneumococcal Disease For Clinicians – Diagnosis and Medical Management. Sept. 6, 2017

126 CDC Pneumococcal Disease - Diagnosis and Treatment. Sept. 6, 2017

127 World Health Organization.  Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics Feb. 27, 2017

128 Harboe ZB, Larsen MV, Ladelund S, et al.  Incidence and Risk Factors for Invasive Pneumococcal Disease in HIV-Infected and Non-HIV-Infected Individuals Before and After the Introduction of Combination Antiretroviral Therapy:  Persistent High Risk Among HIV-Infected Injecting Drug Users. Clin Infect Dis.  2014; 59(8): 1168-76.

129 CDC Pneumococcal Disease - Diagnosis and Treatment. Sept. 6, 2017

130 The MNT Editorial Team What are the Treatment Options for Pneumococcal Disease? MedicalNewsToday. Jan. 5, 2018

131 FDA Combating Antibiotic Resistance. Sept. 10, 2018

132 CDC ANTIBIOTIC RESISTANCE THREATS in the United States, 2013. – Drug Resistant Streptococcus Pneumoniae 2013. Page 79.

133 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

134 Ibid

135 Cecil RL, Austin JH RESULTS OF PROPHYLACTIC INOCULATION AGAINST PNEUMOCOCCUS IN 12,519 MEN J Exp Med. 1918 Jul 1; 28(1): 19–41.

136 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

137 Cecil RL, Austin JH RESULTS OF PROPHYLACTIC INOCULATION AGAINST PNEUMOCOCCUS IN 12,519 MEN J Exp Med. 1918 Jul 1; 28(1): 19–41.

138 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

139 Cecil RL, Austin JH RESULTS OF PROPHYLACTIC INOCULATION AGAINST PNEUMOCOCCUS IN 12,519 MEN J Exp Med. 1918 Jul 1; 28(1): 19–41.

140 Cecil RL, Vaughan HF RESULTS OF PROPHYLACTIC VACCINATION AGAINST PNEUMONIA AT CAMP WHEELER. J Exp Med. 1919 May 1; 29(5): 457–483.

141 Chien YW, Keith P. Klugman KP, Morens DM Efficacy of Whole-Cell Killed Bacterial Vaccines in Preventing Pneumonia and Death during the 1918 Influenza Pandemic J Infect Dis. 2010 Dec 1; 202(11): 1639–16438.

142 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

143 Ekwurzel GM, Simmons JS, Dublin LI, Felton LD. Studies on immunizing substances in pneumococci. VIII. Report on field tests to determine the prophylactic value of a pneumococcus antigen. Public Health Rep 1938; 53: 1877–1893.

144 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

145 Smillie WG, Warnock GH, White HJ A Study of a Type I Pneumococcus Epidemic at the State Hospital at Worcester, Mass Am J Public Health Nations Health. 1938 Mar; 28(3): 293–302.

146 MacLeod CM, Hodges RG, Heidelberger M et al. PREVENTION OF PNEUMOCOCCAL PNEUMONIA BY IMMUNIZATION WITH SPECIFIC CAPSULAR POLYSACCHARIDES J Exp Med. 1945 Nov 30; 82(6): 445–465.

147 KAUFMAN P. Pneumonia in old age; active immunization against pneumonia with pneumonococcus polysaccharide; results of a six year study. Arch Intern Med (Chic). 1947 May;79(5):518-31.

148 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

149  Heidelberger M, MacLeod CM, Di Lapi MM THE HUMAN ANTIBODY RESPONSE TO SIMULTANEOUS INJECTION OF SIX SPECIFIC POLYSACCHARIDES OF PNEUMOCOCCUS J Exp Med. 1948 Sep 1; 88(3): 369–372.

150 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

151 US Office of Technology Assessment. A review of selected federal vaccine and immunization policies: based on case studies of pneumococcal vaccine. Washington, DC: Office of Technology Assessment, September 1979:1–208. P. 32

152 Austrian R. The Jeremiah Metzger Lecture: Of gold and pneumococci: a history of pneumococcal vaccines in South Africa. Trans Am Clin Climatol Assoc. 1978; 89: 141–161.

153 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

154 US Office of Technology Assessment. A review of selected federal vaccine and immunization policies: based on case studies of pneumococcal vaccine. Washington, DC: Office of Technology Assessment, September 1979:1–208. P. 32

155 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

156 US Office of Technology Assessment. A review of selected federal vaccine and immunization policies: based on case studies of pneumococcal vaccine. Washington, DC: Office of Technology Assessment, September 1979:1–208. P. 32

157 CDC Recommendations of the Public Health Service Advisory Committee on Immunization Practices Pneumococcal Polysaccharide Vaccine. MMWR Jan 17, 1978; 27 (4) 25-31

158 US Office of Technology Assessment. A review of selected federal vaccine and immunization policies: based on case studies of pneumococcal vaccine. Washington, DC: Office of Technology Assessment, September 1979:1–208. P. 32

159 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

160 CDC Recommendations of the Immunization Practices Advisory Committee (ACIP) Update: Pneumococcal Polysaccharide Vaccine Usage – United States. MMWR May 25, 1984;33(20) 273-281

161 Ibid

162 CDC Prevention of Pneumococcal Disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Apr. 4, 1997; 46(RR-08);1-24

163 Ibid

164 Ibid

165 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect. 2012 Oct;18 Suppl 5:15-24

166 FDA Pneumococcal 7-Valent Conjugate Vaccine (PREVNAR) - Product Manufacturer Insert.  Oct 1, 2002

167 FDA February 17, 2000 Approval Letter – Prevnar Feb. 17, 2000

168 Ibid

169 CDC ACIP vote regarding pneumococcal conjugate vaccine. Press Release. Jun. 26, 2000

170 O'Reiley T. Vaccine Tops Sales Chart. March 4, 2001. Daily Record (Morris County, NJ).

171 CDC THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) VOTES TO TEMPORARILY REVISE RECOMMENDATIONS FOR PNEUMOCOCCAL CONJUGATE VACCINE AND VOTES TO CONTINUE PREVIOUSLY ISSUED DTaP RECOMMENDATIONS. Press Release. Dec 10, 2001

172 CDC Notice to Readers: Pneumococcal Conjugate Vaccine Shortage Resolved MMWR Sep. 17, 2004; 53(36);851-852

173 FDA October 1, 2002 Approval Letter – Prevnar. Oct 1, 2002

174 FDA Pneumococcal 7-Valent Conjugate Vaccine (PREVNAR) - Product Manufacturer Insert.  Oct 1, 2002

175 Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease following pneumococcal vaccination: A discussion of the evidence. Lancet. 2011 Dec 3; 378(9807): 1962–1973.

176 Associated Press. Shot may be inadvertently boosting superbugs. NBC NEWS Sep. 17, 2007

177 Singleton RJ, Hennessy TW, Bulkow LR, et al Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA. 2007 Apr 25;297(16):1784-92.

178 Ardanuy C, Tubau F, Pallares R, et al. Epidemiology of invasive pneumococcal disease among adult patients in barcelona before and after pediatric 7-valent pneumococcal conjugate vaccine introduction, 1997-2007. Clin Infect Dis. 2009 Jan 1;48(1):57-64.

179 Muñoz-Almagro C, Jordan I, Gene A, et al. Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis. 2008 Jan 15;46(2):174-82

180 Fenoll A, Granizo JJ, Aguilar L et al. Temporal Trends of Invasive Streptococcus pneumoniae Serotypes and Antimicrobial Resistance Patterns in Spain from 1979 to 2007. J Clin Microbiol. 2009 Apr; 47(4): 1012–1020.

181 GlaxoSmithKline Synflorix™, GlaxoSmithKline’s pneumococcal vaccine, receives European authorization. Press Release. Mar. 31, 2009

182 FDA February 24, 2010 Approval Letter - Prevnar 13. Feb. 24, 2010

183 CDC Licensure of a 13-Valent Pneumococcal Conjugate Vaccine (PCV13) and Recommendations for Use Among Children --- Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. Mar. 12, 2010; 59(09);258-261

184 Ibid

185 CDC Prevention of Pneumococcal Disease Among Infants and Children --- Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Dec. 10, 2010; 59(RR11);1-18

186 FDA January 25, 2013 Approval Letter - Prevnar 13. Jan 25, 2015.

187 FDA December 30, 2011 Approval Letter - Prevnar 13. Dec. 30, 2011

188 FDA Accelerated Approval. Jan 4, 2018

189 FDA December 30, 2011 Approval Letter - Prevnar 13. Dec. 30, 2011

190 CDC Licensure of 13-Valent Pneumococcal Conjugate Vaccine for Adults Aged 50 Years and Older. MMWR. Jun 1, 2012; 61(21);394-395

191 Ibid

192 CDC Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Oct. 12, 2012; 61(40);816-819

193 FDA July 11, 2016 Approval Letter - Prevnar 13 July 11, 2016

194 CDC Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Sep. 19, 2014; 63(37);822-825

195 CDC ACIP Meeting Presentation. Incidence of non-Invasive Pneumococcal Pneumonia before and after PCV13 recommendation for adults ≥65yo. Mr. Ryan Gierke. CDC/NCIRD. Oct. 24, 2018

196 Crawford, C ACIP Approves New Guidance on HPV, Pneumococcal Vaccines AAFP Jul. 3, 2019

197 Lee GM, Kleinman K, Pelton S et al. Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period. Pediatrics. 2017 Nov;140(5).

198 Bender, K Pneumococcal Colonization Adapts to Vaccination, Antibiotics. MD Magazine. Dec. 1, 2017

199 Lee LH, Gu XX, Nahm MH Towards New Broader Spectrum Pneumococcal Vaccines: The Future of Pneumococcal Disease Prevention Vaccines (Basel). 2014 Mar; 2(1): 112–128.

200 Choe YJ, Lee HJ, Lee H et al. Emergence of antibiotic-resistant non-vaccine serotype pneumococci in nasopharyngeal carriage in children after the use of extended-valency pneumococcal conjugate vaccines in Korea. Vaccine. 2016 Sep 14; 34(40):4771-6.

201 Su LH,  Kuo AJ, Chia JH et al. Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization Sci Rep. 2015; 5: 15843.

202 Tin Tin Htar M, Christopoulou D, Schmitt HJ Pneumococcal serotype evolution in Western Europe. BMC Infect Dis. 2015; 15: 419.

203 Lee GM, Kleinman K, Pelton S et al. Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period. Pediatrics. 2017 Nov;140(5).

204 Lee LH, Gu XX, Nahm MH Towards New Broader Spectrum Pneumococcal Vaccines: The Future of Pneumococcal Disease Prevention Vaccines (Basel). 2014 Mar; 2(1): 112–128.

205 Choe YJ, Lee HJ, Lee H et al. Emergence of antibiotic-resistant non-vaccine serotype pneumococci in nasopharyngeal carriage in children after the use of extended-valency pneumococcal conjugate vaccines in Korea. Vaccine. 2016 Sep 14; 34(40):4771-6.

206 Su LH,  Kuo AJ, Chia JH et al. Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization Sci Rep. 2015; 5: 15843.

207 Tin Tin Htar M, Christopoulou D, Schmitt HJ Pneumococcal serotype evolution in Western Europe. BMC Infect Dis. 2015; 15: 419.

208 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent Package Insert Dec 30, 2014

209 Smit P, Oberholzer D, Hayden-Smith S, et al. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA. 1977 Dec 12; 238(24):2613-6.

210 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent. Package Insert Dec 30, 2014

211 Simberkoff MS, Cross AP, Al-Ibrahim M et al. Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986 Nov 20; 315(21):1318-27.

212 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent. Package Insert Dec 30, 2014

213 CDC Recommendations of the Immunization Practices Advisory Committee (ACIP) Update: Pneumococcal Polysaccharide Vaccine Usage – United States. MMWR May 25, 1984;33(20) 273-281

214 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent. Dec 30, 2014

215 Ibid

216 Jackson LA, Janoff EN. Pneumococcal vaccination of elderly adults: new paradigms for protection. Clin Infect Dis. 2008 Nov 15; 47(10):1328-38.

217 Johnstone J, Eurich DT, Minhas JK et al. Impact of the pneumococcal vaccine on long-term morbidity and mortality of adults at high risk for pneumonia. Clin Infect Dis. 2010 Jul 1; 51(1):15-22.

218 Kumar D, Chen MH, Welsh B et al. A randomized, double-blind trial of pneumococcal vaccination in adult allogeneic stem cell transplant donors and recipients. Clin Infect Dis. 2007 Dec 15;45(12):1576-82

219 Hung CC, Chang SY, Su CT et al A 5-year longitudinal follow-up study of serological responses to 23-valent pneumococcal polysaccharide vaccination among patients with HIV infection who received highly active antiretroviral therapy. HIV Med. 2010 Jan;11(1):54-63.

220 Yasumori I Manabu A, Yukihiro A et al The 23-valent pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis: a double-blinded, randomized, placebo-controlled trial Arthritis Res Ther. 2017; 19: 15.

221 FDA Prevnar 13 Package Insert Aug 22, 2017

222 Ibid

223 Ibid

224 Ibid

225 Pichichero ME, Casey JR, Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 2007 Oct 17; 298(15):1772-8.

226 Moore MR, Gertz RE Jr, Woodbury RL et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis. 2008 Apr 1;197(7):1016-27

227 Burgos J1, Lujan M, Falcó V, et al. The spectrum of pneumococcal empyema in adults in the early 21st century. Clin Infect Dis. 2011 Aug 1;53(3):254-61

228 Fletcher, MA, Schmitt HJ, Syrochkina M et al. Pneumococcal empyema and complicated pneumonias: global trends in incidence, prevalence, and serotype epidemiology. Eur J Clin Microbiol Infect Dis. 2014; 33(6): 879–910.

229 Shen CF, Wang SM, Lee KH et al. Childhood invasive pneumococcal disease caused by non-7-valent pneumococcal vaccine (PCV7) serotypes under partial immunization in Taiwan. J Formos Med Assoc. 2013 Sep;112(9):561-8

230 Byington CL, Korgenski K, Daly J et al. Impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema. Pediatr Infect Dis J. 2006 Mar; 25(3):250-4.

231 CDC Farrell DJ, Klugman KP, Pichichero M. Increased antimicrobial resistance among nonvaccine serotypes of Streptococcus pneumoniae in the pediatric population after the introduction of 7-valent pneumococcal vaccine in the United States. Pediatr Infect Dis J. 2007 Feb; 26(2):123-8.

232 Singleton RJ, Hennessy TW, Bulkow LR et al. Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA. 2007 Apr 25; 297(16):1784-92.

233 Hsu HE, Shutt KA, Moore MR, et al. Effect of Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis. N Engl J Med. 2009 Jan 15; 360(3): 244–256.

234 Diawara I, Zerouali K, Elmdaghri N et al. A case report of parapneumonic pleural effusion caused by Streptococcus pneumoniae serotype 19A in a child immunized with 13-valent conjugate pneumococcal vaccine. BMC Pediatr. 2017; 17: 114.

235 Antachopoulos C, Tsolia MN, Tzanakaki G, et al Parapneumonic pleural effusions caused by Streptococcus pneumoniae serotype 3 in children immunized with 13-valent conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2014 Jan;33(1):81-3

236 Syrogiannopoulos GA, Michoula AN, Tsimitselis G et al. Pneumonia with empyema among children in the first five years of high coverage with 13-valent pneumococcal conjugate vaccine. Infect Dis (Lond). 2016 Oct;48(10):749-53.

237 Silva-Costa C, Brito MJ, Pinho MD, et al. Pediatric Complicated Pneumonia Caused by Streptococcus pneumoniae Serotype 3 in 13-Valent Pneumococcal Conjugate Vaccinees, Portugal, 2010-2015. Emerg Infect Dis. 2018 Jul;24(7):1307-1314

238 Lee LH, Gu XX, Nahm MH Towards New Broader Spectrum Pneumococcal Vaccines: The Future of Pneumococcal Disease Prevention Vaccines (Basel). 2014 Mar; 2(1): 112–128.

239 Su LH,  Kuo AJ, Chia JH et al. Evolving pneumococcal serotypes and sequence types in relation to high antibiotic stress and conditional pneumococcal immunization Sci Rep. 2015; 5: 15843.

240 Choe YJ, Lee HJ, Lee H et al. Emergence of antibiotic-resistant non-vaccine serotype pneumococci in nasopharyngeal carriage in children after the use of extended-valency pneumococcal conjugate vaccines in Korea. Vaccine. 2016 Sep 14; 34(40):4771-6.

241 Tin Tin Htar M, Christopoulou D, Schmitt HJ Pneumococcal serotype evolution in Western Europe. BMC Infect Dis. 2015; 15: 419.

242 Büyükcam A, Güdücüoğlu H, Karaman K et al. Invasive pneumococcal infection due to serotype 15A after the pneumococcal conjugate vaccine implementation in Turkey. Hum Vaccin Immunother. 2017 Aug 3; 13(8):1892-1894.

243 Steens A, Bergsaker MA, Aaberge IS et al. Prompt effect of replacing the 7-valent pneumococcal conjugate vaccine with the 13-valent vaccine on the epidemiology of invasive pneumococcal disease in Norway. Vaccine. 2013 Dec 16; 31(52):6232-8.

244 Lee GM, Kleinman K, Pelton S et al. Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period. Pediatrics. 2017 Nov; 140(5).

245 Bender, K Pneumococcal Colonization Adapts to Vaccination, Antibiotics. MD Magazine. Dec. 1, 2017

246 Murphy TF. Vaccines for Nontypeable Haemophilus influenzae: the Future Is Now Clin Vaccine Immunol. 2015 May; 22(5): 459–466.

247 Weinberger DM, Malley R, Lipsitch M Serotype replacement in disease following pneumococcal vaccination: A discussion of the evidence. Lancet. 2011 Dec 3; 378(9807): 1962–1973.

248 Ibid

249 Lehmann D, Willis J, Moore HC et al The changing epidemiology of invasive pneumococcal disease in aboriginal and non-aboriginal western Australians from 1997 through 2007 and emergence of nonvaccine serotypes. Clin Infect Dis. 2010 Jun 1;50(11):1477-86

250 Hanna JN, Humphreys JL, Murphy DM. Invasive pneumococcal disease in Indigenous people in north Queensland: an update, 2005-2007. Med J Aust. 2008 Jul 7; 189(1):43-6.

251 CDC ACIP Meeting Presentation. Incidence of non-Invasive Pneumococcal Pneumonia before and after PCV13 recommendation for adults ≥65yo. Mr. Ryan Gierke. CDC/NCIRD. Oct. 24, 2018

252 Crawford, C ACIP Approves New Guidance on HPV, Pneumococcal Vaccines AAFP Jul. 3, 2019

253 Greenberg D, Hoover PA, Vesikari T et al. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants. Vaccine. 2018 Oct 29;36(45):6883-6891

254 Sagonowsky, E Racing with Merck, Pfizer wins FDA 'breakthrough' tag for 20-valent pneumococcal vaccine. Fierce Pharma. Sep. 20, 2018

255 FDA Breakthrough Therapy. Jan 4, 2018

256 CDC Pneumococcal Conjugate (PCV13) VIS. Nov. 5, 2015

257 CDC Pneumococcal Polysaccharide VIS. Apr. 24, 2015

258 CDC Pneumococcal Conjugate (PCV13) VIS. Nov. 5, 2015

259 FDA Prevnar 13 Package Insert Aug. 22, 2017

260 Ibid

261 Ibid

262 FDA Pneumococcal 7-Valent Conjugate Vaccine (PREVNAR) - Product Manufacturer Insert.  Oct 1, 2002

263 Hitt, E Prevnar 13 Should Be Watched for Febrile Seizure Risk, FDA Panel Says. Medscape. Jan 31, 2012

264 Tse A, Tseng HF, Greene SK, et al. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012 Mar 2;30(11):2024-31

265 Baker M, Jankosky C, Yih K et al. The Risk of Febrile Seizures Following Influenza and 13-Valent Pneumococcal Conjugate Vaccines. Open Forum Infect Dis. 2017 Fall; 4(Suppl 1): S464–S465.

266 CDC Childhood Vaccines and Febrile Seizures Jun. 20, 2016

267 Ibid

268 Ravishankar,N Guillain-Barre Syndrome Following PCV Vaccine. J Neurol Neurosurg 4(1): 134

269 Tawfik P, Elie Gertner E, McEvoy CE Severe polyserositis induced by the 13-valent pneumococcal conjugate vaccine: a case report J Med Case Rep. 2017; 11: 142.

270 DeRogatis MJ, Parameswaran L, Lee P et al. Septic Shoulder Joint After Pneumococcal Vaccination Requiring Surgical Debridement. HSS J. 2018 Oct;14(3):299-301

271 Monastirli A, Pasmatzi E, Badavanis G et al. Erythema multiforme following pneumococcal vaccination. Acta Dermatovenerol Alp Pannonica Adriat. 2017 Mar;26(1):25-26.

272 CDC Pneumococcal Polysaccharide VIS. Apr. 24, 2015

273 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent. Package Insert Dec 30, 2014

274 Ibid

275 Ibid

276 Ibid

277 von Elten, KA, Duran LL, Banks TA, et al. Systemic inflammatory reaction after pneumococcal vaccine A case series Hum Vaccin Immunother. 2014 Jun 1; 10(6): 1767–1770.

278 Huang DT, Chiu NC, Chi H, et al. Protracted fever with cellulitis-like reaction in pneumococcal polysaccharide-vaccinated children. Pediatr Infect Dis J. 2008 Oct;27(10):937-9.

279 Yousef E, Mannan S. Systemic reaction to pneumococcal vaccine: how common in pediatrics? Allergy Asthma Proc. 2008 Jul-Aug;29(4):397-9

280 Gabor EP, Seeman M. Acute febrile systemic reaction to polyvalent pneumococcal vaccine. JAMA. 1979 Nov 16;242(20):2208-9.

281  Hasan S, Yousef M, Shridharani S Severe febrile systemic reaction to pneumococcal vaccine. J Natl Med Assoc. 2005 Feb; 97(2): 284–285.

282 Lee A, Goyal R, Shan HY. Severe protracted fever following pneumococcal vaccine. Am J Med Sci. 2006 Dec;332(6):351-3.

283 Kessler DA, the Working Group, Natanblut S, et al. A New Approach to Reporting Medication and Device Adverse Effects and Product Problems. JAMA. 1993;269(21):2765-2768.

284 FDA.gov. Kessler DA. Introducing MEDWatch: A New Approach to Reporting Medication and Device Adverse Effects and Product Problems. Reprint from JAMA. June 9, 1993.

285 Braun M. Vaccine adverse event reporting system (VAERS): usefulness and limitations. Johns Hopkins Bloomberg School of Public Health

286 Rosenthanl S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health 1995; 85: pp. 1706-9.

287 AHRQ Electronic Support for Public Health–Vaccine Adverse Event Reporting System (ESP:VAERS) Dec 1, 2007-Sep. 30, 2010

288 U.S. Department of Health and Human Services. National Vaccine Injury Compensation Program Data—July 1, 2019. National Vaccine Injury Compensation Program. Jul. 1, 2019

289 Health Resources & Services Administration (HRSA) Covered Vaccines. June 2019

290 Tse A, Tseng HF, Greene SK, et al Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012 Mar 2;30(11):2024-31.

291 Duffy J, Weintraub E, Hambidge SJ, et al. Febrile Seizure Risk After Vaccination in Children 6 to 23 Months. Pediatrics. 2016 Jul;138(1).

292 Jackson LA, Benson P, Sneller VP et al. Safety of revaccination with pneumococcal polysaccharide vaccine. JAMA. 1999 Jan 20;281(3):243-8.

293 CDC Pneumococcal Conjugate (PCV13) VIS. Nov. 5, 2015

294 CDC Pneumococcal Polysaccharide VIS. Apr. 24, 2015

295 FDA Prevnar 13 Package Insert Aug. 22, 2017

296 FDA Pneumovax 23 - Pneumococcal Vaccine, Polyvalent. Package Insert Dec 30, 2014


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