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What is the history of Chickenpox vaccine use in America and other countries?

Updated July 30, 2023

vaccine history

The first live attenuated chickenpox vaccine was developed by Dr. Michiaki Takahashi in Japan. The virus was isolated from the fluid-filled blisters of a three-year-old child with typical chickenpox illness.  The Oka strain of the chickenpox virus, named after the family from whom the virus was acquired,  was then cultivated in guinea-pig embryo cultures and tested on a small number of children between 1 and 10 years of age. Scientists further developed the vaccine by taking the attenuated virus previously cultivated in guinea-pig embryo cultures and propagating it in WI-38 cells,  a human diploid cell line derived from the lung tissue of an aborted three-month human female embryo. 

Takahaski’s experimental chickenpox vaccine was initially tested in 1974 on 23 susceptible children, after a case of chickenpox occurred in the children’s ward of a local hospital.  Six of the 23 children developed a fever following vaccination, and two of the six children also developed a mild rash. Study researchers reported uncertainty to whether the fever and rash were vaccine-related or related to a natural chickenpox infection modified by the administration of the vaccine. After vaccinating an additional 16 children with a diagnosis of kidney disease and reporting both the presence of antibodies considered protective against chickenpox and an absence of adverse reactions, researchers declared the vaccine safe for use in hospitalized children. 

Additional clinical trials involving both healthy and hospitalized children were completed       and in 1986, the Japanese government approved the vaccine for use in persons 12 months of age and older. 

Meanwhile, in the United States, scientists working for Merck had isolated and attenuated a different chickenpox virus strain, the KMcC strain, but were unable to produce results similar to those observed after Oka strain vaccine administration.  One study involving 369 healthy children found that those who received the KMcC chickenpox strain reacted significantly and “unacceptably”   higher than those who were administered the OKA strain.  In 1981, Merck licensed Japan’s Oka varicella virus strain and further attenuated the strain in MRC-5 cells – cells derived from lung tissue taken from a 14 week old male aborted fetus  - prior to starting pre-licensure clinical trials in 1982.   

Clinical trials of Varivax, Merck’s live, attenuated chickenpox virus vaccine, involved the use of different vaccine lots manufactured between 1982 and 1991. Manufacturing of the vaccine, however, changed several times, to increase the amount, stability and viability of the live virus and each vaccine lot contained a different amount of the live virus (plaque forming units or PFU), and varying ratios of live and dead viral antigens. 

Only one double-blind, placebo-controlled study of the chickenpox vaccine was ever completed; however, the vaccine involved in this trial was not the formulation which eventually received FDA approval. This particular trial began in 1982 and involved 956 healthy children, 468 who received a chickenpox vaccine, and 446 who received a placebo. The experimental vaccine in this study contained 17,430 PFU while the placebo consisted of a lyophilized stabilizer containing at least 45 mg of neomycin. 

Vaccine researchers reported that no cases of chickenpox occurred among vaccine recipients within the first year; however, 0.6 percent developed the illness in the second year. 8.5 percent of children in the placebo control group developed chickenpox within the first year. Vaccine recipients reported a significantly higher rate of swelling, pain and redness to the injection site in comparison to those who received the placebo.  An additional clinical trial in 1982 involved the use of an experimental chickenpox vaccine containing 950 PFU but within two years, this vaccine had an efficacy of only 72 percent. 

In 1984, Merck began another clinical trial involving 1,300 healthy participants who received experimental vaccine doses which contained anywhere from 2,460 to 14,000 PFU of attenuated chickenpox virus. Few study participants were actively followed, and researchers relied on parents to contact them to report breakthrough infections of chickenpox. 

A 1987 study of an experimental vaccine which contained between 1,000 – 1,625 PFU of attenuated chickenpox virus involved 4,142 healthy children; however, researchers found that after 2 years, this formulation had an efficacy of only between 61 and 67 percent. The final pre-licensing clinical trial, which began in 1991, used vaccines with formulations of between 2,900 and 9,000 PFU. The vaccines used in this clinical trial were considered to be nearly identical to Varivax, the vaccine which eventually received FDA approval and is still currently in use in the United States. The trial involved only 1,164 participants and after a follow up period of 3 years, Merck reported that the vaccine was 93 percent effective against chickenpox illness. 

The safety evaluation of Varivax chickenpox vaccine was completed by combining the safety data collected from all five pre-licensing clinical trials; however, only side effects which occurred at a rate of over one percent of all trial participants within 42 days of vaccine administration were included in the report. Of the 9,230 healthy vaccine recipients involved the trials, 62.5 percent experienced an upper respiratory illness and 40.4 percent reported a cough within 42 days of vaccination. Additional reported side effects included irritability/nervousness, sleep disturbance, fatigue, diarrhea, loss of appetite, and injection site complaints. The injection site complaints included pain, swelling, inflammation, itching and chickenpox-like rash. 

Merck’s live chickenpox virus vaccine, Varivax, received FDA approval for use in March 1995 and each 0.5mL dose was reported to contain no less than 1,500 PFU of Merck/Oka varicella virus or no less than 1,350 PFU up to 30 minutes following reconstitution of the vaccine. Additional vaccine ingredients included monosodium-L-glutamate (MSG), sodium phosphate dibasic, potassium phosphate monobasic, potassium chloride, trace quantities of sodium phosphate monobasic, EDTA, neomycin, sucrose, hydrolyzed gelatin, sodium chloride, residual components of MRC-5 cells, and fetal bovine serum. 

The FDA’s summary review of Varivax reported that the MRC-5 cells in Varivax vaccine contained unusual DNA. Prior to the vaccine’s licensure, the FDA expressed concerns that this residual DNA might potentially integrate into and change the cells of the vaccine recipient. However, after further evaluation, the FDA decided that the presence of approximately 2ug of cellular DNA in each vaccine dose would likely not cause harm and “that this anomaly did not pose a safety risk which exceeded the known benefit of the vaccine.” 

The FDA summary report also noted the potential for vaccine recipients to transmit the vaccine virus to susceptible contacts and warned of the need for recently vaccinated persons to avoid contact with non-immune pregnant women and other susceptible high-risk individuals for several weeks post-vaccination. 

The FDA also admitted that widespread use of the chickenpox vaccine could result in an increase in shingles infections. After chickenpox illness, the chickenpox virus will remain dormant in the sensory nerve ganglia of the body but can re-activate as shingles (herpes zoster) - a painful skin rash which often develops on one side of the body or face.  Complications from shingles include balance or hearing issues, vision loss, and post herpetic neuralgia (PHN) - a severe and frequently long-lasting pain at the shingles rash site.  Stating that scientific evidence suggested exposure to natural chickenpox decreased the risk of shingles, the FDA recommended careful monitoring of shingles rates post-vaccine licensure, to detect any changes. 

In the spring of 1996, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted to routinely recommend Merck’s live virus chickenpox vaccine, Varivax. In its formal recommendation published on July 12, 1996, ACIP recommended that all children without a prior history of chickenpox illness receive a single dose of the chickenpox vaccine beginning at 12 months of age. ACIP also recommended that all children 12 and under with no prior history of chickenpox illness receive a single dose of chickenpox vaccine. Persons 13 years and older with no prior history of illness were advised to receive two vaccine doses, administered 4-8 weeks apart. 

The CDC acknowledged that recently vaccinated individuals could potentially transmit the infection to susceptible individuals, including immunocompromised household members; however, they reported that the benefit of vaccination would outweigh this potential risk. The vaccine, however, was not approved for use in persons with immune disorders such as HIV, AIDS, leukemia, lymphoma, blood disorders, lymphomas of any type, other malignant conditions which affected the lymphatic systems or bone marrow, pregnant women, nursing mothers, and persons with a family history of congenital immunodeficiency. Individuals with acute lymphoblastic leukemia (ALL) could, however, receive the vaccine free of charge from Merck as part of a research protocol, if they met certain predetermined criteria. 

The cost-effectiveness analysis of implementing this recommendation was based on both direct medical costs and indirect costs associated with chickenpox illness. The analysis found that vaccinating all children with one dose of chickenpox vaccine could not be considered cost-effective if only medical costs were taken into consideration. When the indirect costs associated with loss of income (i.e. parent required to stay at home with a sick child) were included in the analysis, the CDC determined that routine chickenpox vaccination would be cost effective.  The CDC declined to include any data on the potential costs associated with a rise in shingles cases among persons with a history of natural chickenpox illness or even among vaccinated children, and assumed that the implementation of the chickenpox vaccine program would not impact shingles rates. 

In 1996, at the time of the CDC’s ACIP recommendation for routine administration of the newly licensed chickenpox vaccine, it was estimated that approximately 3.7 million cases of chickenpox occurred annually. However, as the illness was not nationally notifiable, the CDC acknowledged their surveillance data to be limited and ineffective to monitor the vaccine’s impact on chickenpox rates.  In response, the CDC established three active chickenpox surveillance sites, in Antelope Valley, California, Travis County, Texas and West Philadelphia, PA.  The CDC also recommended that state legislatures begin planning the implementation of chickenpox vaccine requirements for daycare, Head Start, and school entry, once the vaccine’s supply was considered adequate. 

In February 1999, ACIP formally recommended that all states require proof of vaccination or immunity to chickenpox for both daycare and school entry, including middle school entry. The middle school requirement was made to reduce the risk of children reaching adulthood without immunity to chickenpox. ACIP also expanded chickenpox vaccine recommendations to include asymptomatic or mildly symptomatic HIV-positive children and children with impaired humoral immunity. Additionally, the chickenpox vaccine was recommended for use in susceptible individuals within 3 to 5 days of exposure to chickenpox, to prevent or reduce severity of the illness. 

According to the CDC, by 2000, as chickenpox vaccination rates increased to between 74 and 84 percent of all 19 to 35-month olds within the active surveillance site communities (Antelope Valley, California, Travis County, Texas and West Philadelphia, PA), chickenpox infections decreased significantly.  

The CDC, however, chose not to monitor shingles infections at any of the three active surveillance sites set up in 1995 to evaluate the impact of the chickenpox vaccine. Five years later, in 2000, shingles surveillance was finally added to California’s Antelope Valley Varicella Active Surveillance Project (AV-VASP), at a time when chickenpox infection rates had declined by 70 percent. By 2000, the number of reported shingles infections had already increased dramatically in adults 20 to 69 years of age. Further, children with a prior history of natural chickenpox infection were found to have shingles rates similar adults.  Over a three-year period, between 2000 and 2002, the number of reported shingles cases increased by 56 percent (an 18 percent yearly increase). 

Gary Goldman, Research and Epidemiology Analyst at AV-VASP, reported his shingles findings to multiple entities, including the CDC, site project investigators, Merck, and the FDA; however, the CDC chose to ignore his data and declined to publish any potential information suggesting that the chickenpox vaccine had resulted in an overwhelming increase in the number of shingles cases. Goldman resigned from AV-VASP on October 18, 2002, stating that “When research data concerning a vaccine used in human populations is being suppressed and/or misrepresented, this is very disturbing and goes against all scientific norms and compromises professional ethics.” 

Goldman’s findings were not unique. In 2005, a CDC sponsored study was published on shingles rates in Massachusetts. This study found that between 1998 and 2003, as chickenpox vaccine rates increased and chickenpox infection rates decreased, the overall rate of shingles infections increased by 141 percent among all age groups. The incidence of shingles among adults between 25 and 44 years increased by 161 percent while rates among children and young adults aged one to 24 years increased by 152 percent. 

As vaccination rates increased to approximately 90 percent, chickenpox infections among vaccinated individuals also increased, from two percent to 56 percent. Between 2001 and 2005, multiple chickenpox outbreaks among vaccinated school children were reported and vaccinated students were often found to be responsible for outbreaks. The vaccine was estimated by the CDC to be between 72 and 85 percent effective, however, one school reported that 40 percent of vaccinated school children in a particular classroom had developed chickenpox. While many cases of chickenpox were reported to be mild, up to 30 percent were not, and vaccinated children developed symptoms similar to those seen in children who experienced a natural chickenpox infection.  By October of 2004, in response to the growing number of outbreaks among vaccinated school children, ACIP began discussions on the implementation of a second dose of chickenpox vaccine. 

In September 2005, Merck received FDA approval for ProQuad (MMRV), a live virus vaccine containing measles, mumps, rubella, and varicella (chickenpox) antigens, for use in children 12 months to 12 years of age. ProQuad received approval without any formal clinical efficacy trials, as Merck was permitted by the FDA to submit data to show that the antibody response to ProQuad was not inferior to that of Varivax and MMRII administered simultaneously at separate injection sites. 

According to the FDA’s clinical summary report to support ProQuad vaccine licensure, five vaccine trials involving over 1,600 children occurred in the 1980s and early 1990s. From these early clinical trials, Merck discovered that while the immune responses to measles, mumps, and rubella were similar to those seen after MMRII vaccination, the immune response to the chickenpox antigen was low and inadequate. In response, ProQuad was reformulated with a higher amount of chickenpox virus. 

Five additional pre-licensing clinical trials were submitted to the FDA in support of ProQuad licensure, but no studies compared ProQuad to an inert placebo. Instead, clinical trials compared different formulations of ProQuad containing varying amounts of chickenpox virus to the administration of MMRII and Varivax vaccines given concomitantly; the safety and immunogenicity of one versus two doses of a ProQuad vaccine containing a high amount of chickenpox virus; the safety and tolerance of three different lots of ProQuad when compared with MMRII and Varivax vaccines administered concomitantly; the safety and immunogenicity of administering ProQuad in combination with Tripedia (Diphtheria, Tetanus, and whole cell Pertussis vaccine) and Comvax (combined Haemophilus Influenzae Type B and Hepatitis B vaccine) versus the administration of ProQuad followed by Tripedia and Comvax; and the immunogenicity of ProQuad when administered to healthy 4-6 year old children. 

In pre-licensing clinical trials, 81.5 percent of children who received ProQuad and 79.6 percent of children who received MMRII and Varivax concomitantly reported at least one or more adverse events after vaccine administration. Further, 76.1 percent of children who received ProQuad and 72.3 percent of children who received MMRII and Varivax reported systemic adverse reactions which included fever, upper respiratory infection, measles-like rash, and chickenpox-like rash. Febrile seizures were also reported, however, per the FDA, the clinical trials “were not designed or powered to detect an increase in the frequency of this low frequency adverse reaction.” 

On December 2, 2005, the CDC published a notice in regards to the licensing of Merck’s measles, mumps, rubella, and varicella (chickenpox) live virus vaccine, ProQuad (MMRV). In this notice, the CDC stated that the newly licensed ProQuad vaccine, approved for use in children 12 months to 12 years of age, could be used in lieu of separate doses of MMR and chickenpox vaccine, and that combination vaccines were preferential to separate doses of equivalent vaccine components. In 2005, all children were recommended to receive two doses of MMR vaccine, with the first dose at 12 to 15 months, and the second dose at 4 to 6 years. At this time, however, only a single dose of chickenpox vaccine was recommended, at 12 to 15 months of age. In this notice, the CDC stated that ProQuad could still be given to children previously vaccinated with Varivax vaccine if the MMR vaccine was not available, the potential benefits to the child outweighed the possible risk of receiving an additional dose of chickenpox vaccine, or in the event of a chickenpox outbreak, where an additional dose of chickenpox vaccine was recommended. 

While acknowledging that little to no data existed to support the safety or effectiveness of administering ProQuad concomitantly with hepatitis A, influenza, DTaP, pneumococcal conjugate (Prevnar), or inactivated polio vaccines, the CDC recommended that ProQuad (MMRV) be administered simultaneously with any recommended vaccines. 

In June 2006, in response to the significant rise of chickenpox illness among vaccinated individuals, ACIP voted to recommend a second dose of chickenpox vaccine for all children prior to school entry, at age 4-6 years. An additional dose of chickenpox vaccine was also recommended for all persons previously vaccinated with one vaccine dose. The CDC stated that adding a second dose of chickenpox vaccine would remain cost-effective but chose not to evaluate cost factors associated with the rise in shingles cases noted after the implementation of the chickenpox vaccination program and reported “that no consistent trends” indicate that the increase could be associated with the use of chickenpox vaccine. 

The chickenpox vaccine supply became problematic for Merck in February 2007, due to manufacturing issues. In response, Merck reported that production of Varivax and its recently approved live virus shingles vaccine, Zostavax, would be prioritized over its ProQuad (MMRV) vaccine. Merck stated that it would be capable of meeting current demands for both Varivax and Zostavax, but by July 2007, their ProQuad (MMRV) vaccine would no longer be available. 

In February 2008, data was presented at the CDC’s ACIP meeting in regards to a link between ProQuad (MMRV) and seizures. The Vaccine Safety Datalink (VSD), a collaborative project between several health care organizations and the CDC’s Immunization Safety Office (ISO), found that children between 12 and 23 months who received ProQuad vaccine were over twice as likely to suffer a seizure 5 to 12 days after vaccine administration when compared with children who received separate doses of MMRII and chickenpox vaccine. ACIP, however, chose not to issue a warning, but instead, revised its MMRV recommendation and stated that they did not "express a preference for use of MMRV vaccine over separate injections of equivalent component vaccines (i.e., MMR vaccine and varicella vaccine)." 

While noting that ProQuad was not likely to become available before 2009, ACIP recommended the formation of a workgroup to evaluate the risk of seizures after MMRV vaccine administration. 

Additional data presented by the workgroup confirmed an increased risk of seizures among children 12 to 23 months of age after MMRV administration when compared to those who received separate doses of MMRII and Varivax vaccines. In response, ACIP advised that for the first dose of measles, mumps, rubella, and varicella vaccine in children between the ages of 12 and 47 months, either MMRII and Varivax or MMRV could be used, unless a personal or family history of seizures existed. MMRV, however, was recommended over separate injections of MMRII and Varivax for the second dose, or for the first vaccine dose in children 48 months and older. In this recommendation, ACIP stated that “Given the balance of risks and benefits of a first dose of MMRV vaccine compared with a first dose of MMR vaccine and varicella vaccine, and the importance of individual values and preferences in weighing these risks and benefits, decisions should be made by providers and parents or caregivers on a case-by-case basis.” 

In 2013, Gary Goldman, the Research and Epidemiology Analyst at California’s Antelope Valley Varicella Active Surveillance Project (AV-VASP) from 1995 to November 2002, published a review of the United States universal chickenpox vaccination program based on his experience at the AV-VASP site. Goldman reported that by 2000, chickenpox infection rates decreased by 70 percent at the AV-VASP site; however, by 2002, the vaccine’s efficacy was found to be less than 80 percent and cases of chickenpox illness were increasing among previously vaccinated individual. Further, between 2000 and 2001, shingles rates significantly increased among adults aged 20 to 69 years and children with a previous history of natural chickenpox illness had shingles rates that were similar to adult rates. From his findings, Goldman reported that shingles “morbidity costs have exceeded the cost savings from varicella-disease reductions.” He also stated that the current vaccination program had failed to eliminate chickenpox illness and had “proven extremely costly.” 

In March 2023, the FDA approved both Varivax and ProQuad to be administered by intramuscular injection (IM), meaning injecting into muscle tissue. This approval is in addition to the previously approved subcutaneous (SC) injection route, meaning under the skin. Intramuscular injection was approved based on small clinical studies conducted by the manufacturer in 2005 showing the antibody responses to be similar between both routes of administration. Clinical trials also reported lower rates of injection site reactions among children who received vaccination by IM injection.   

In their clinical review of the data, the FDA reported that allowing both the Varivax and ProQuad vaccines to be given by both IM and SC would recognize the importance of giving vaccine providers a choice on how to administer the vaccine and would align vaccination of these products with other vaccines. Additionally, the FDA noted that “current clinical recommendations concerning immunization practice do not require reimmunization when a vaccine indicated for the SC route is erroneously given IM (ACIP)”.   

The CDC currently reports that one in three persons in the U.S. will develop shingles at some point in their lives, and the rate is increasing. They report, however, that they do not know why shingles rates are increasing but deny that the chickenpox vaccine is in anyway related to the increase.  The CDC also reports that most cases of chickenpox occur among vaccinated persons but describe the illness as milder, with fewer than 50 lesions and lower rates of fever. They do, however, report that the modified clinical presentation of chickenpox among vaccinated individuals has resulted in diagnosing challenges for both parents and health care providers. 

IMPORTANT NOTE: NVIC encourages you to become fully informed about Chickenpox and the Chickenpox 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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