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What is the history of Pneumococcal vaccine use in America?

vaccine history

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.1

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.2 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.3

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 5.4 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.5

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.6 

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.7 8

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.9

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.10 11

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.12 13

Both military and civilian clinical trials of polysaccharide pneumococcal vaccines reported favorable results,14 15 and in 1947, the first pneumococcal polysaccharide vaccine licenses were granted to E.R. Squibb & Sons.16 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. 17

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.18 19

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;20 however, by 1975, Eli Lilly had terminated its research and development after several issues with the vaccine had occurred.21 22

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.23

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, 1977.24 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.25

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.26

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.27

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. 28  ACIP also continued to recommend that all adults and children 2 and older with chronic illness or immunosuppression receive a dose of the vaccine.29

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.30

As pneumococcal polysaccharide vaccines were found to be ineffective in children under the age of 2, vaccine development continued.31 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.32

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.33

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,34 which seriously compromised the scientific validity of the trial. The vaccine, however, still received approval by the FDA in February of 2000.35

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.36

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.37

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.38

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.39 Issues with vaccine shortages were not completely resolved until September of 2004.40

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.41 42

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,43 most notably, strain 19A, a highly virulent and antibiotic-resistant serotype.44 45 In Spain, an increase in invasive pneumococcal disease occurred following the introduction of PCV7, with the emergence of several non-vaccine type strains.46 47 48

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.49 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.50

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.51

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.52 53 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 2013.54

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.55 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.56

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.57 58

While the ACIP declined to routinely recommend PCV13 for adults over the age of 50 following the FDA’s approval to expand its usage,59 the committee did vote to recommend the vaccine for use in immunocompromised adults 19 years of age and older, in June of 2012.60 The FDA, however, did not approve PCV13 for use in adults 19 to 49 until July 11, 2016.61

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;62 however, by October 2018, ACIP reported that is recommendation had not reduced pneumonia rates among persons 65 years and older.63

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.64

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.65 66 These non-vaccine type strains include strains 33F, 22F, 12, 15B, 15C, and 23 A.67

Korea, 68 Taiwan,69 and several Western European countries, 70 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. 71 72 73 74 75

IMPORTANT NOTE: NVIC encourages you to become fully informed about Pneumococcal and the Pneumococcal vaccine by reading all sections in the Table of Contents , which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.

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References

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

2 Ibid

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

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

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

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

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

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

9 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.

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

11 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.

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

13 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.

14 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.

15 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.

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

17  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.

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

19 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

20 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.

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

22 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

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

24 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

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

26 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

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

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

29 Ibid

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

31 Ibid

32 Ibid

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

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

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

36 Ibid

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

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

39 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

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

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

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

43 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.

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

45 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.

46 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.

47 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

48 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.

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

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

51 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

52 Ibid

53 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

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

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

56 FDA Accelerated Approval. Jan 4, 2018

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

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

59 Ibid

60 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

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

62 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

63 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

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

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

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

67 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.

68 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.

69 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.

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

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

72 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.

73 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.

74 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.

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


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