Statement from the Global Advisory Committee on Vaccine Safety

Statement on risks and benefits of rotavirus vaccines Rotarix and RotaTeq

Two rotavirus vaccines, Rotarix and RotaTeq, are in widespread use globally for the prevention of rotavirus gastroenteritis in young infants. WHO recommends the inclusion of rotavirus vaccine in all country immunization programs. Their use has resulted in reductions of infant diarrheal deaths, hospitalizations and incidence of rotavirus gastroenteritis.^{1, 2} Thus even in countries where mortality rates for rotavirus gastroenteritis are low, there is a substantial health benefit associated with vaccination. ^{3, 4}

An increased risk of intussusception has been found in multiple countries for both vaccines following the first and second dose of the vaccine series (2 doses with Rotarix and 3 doses with RotaTeq), especially within the first 7 days after vaccination. However, the benefits of prevention of rotavirus gastroenteritis have continued to be judged to outweigh risks associated with vaccination, including the risk of intussusception.

In France, a preliminary review of adverse event data also suggested an overall risk of intussusception following rotavirus vaccination. This risk was in the same range as that observed elsewhere. However, French health authorities reported that since rotavirus vaccines had been introduced, they identified two deaths temporally related to intussusception. One was an infant who died at home without receiving medical care 7 days following the first dose of rotavirus vaccine. The other infant death followed a third dose of vaccine. So far, the third dose has not been associated with an increased risk in published studies. As the third dose is usually administered at an age of highest incidence of intussusception, this association is more likely to be a coincidental event.

Death from intussusception following rotavirus vaccine underscores the importance of close monitoring of infants and prompt medical care for signs and symptoms of intussusception any time. This is irrespective of the vaccine product administered. If recognized and treated early, intussusception generally has a good outcome and is rarely fatal. Risks of adverse immunization outcomes due to intussusception can be reduced by early evaluation and treatment of children with symptoms consistent with intussusception.

Based on its reviews over the past several years, including the risk of intussusception, GACVS continues to affirm that the safety profile of current rotavirus vaccines is acceptable, with the benefits of vaccination greatly exceeding risks. The benefits of rotavirus vaccination are particularly important in resource-poor countries where rotavirus disease remains an important cause of mortality among young children.

¹ Patel M, Parashar UD, Santosharm M, Richardson V. The rotavirus experience in Mexico: discovery to control. Clin Infect Dis 2013 Feb 15;56(4):548-51

² Linhares AC, Justino MCA. Rotavirus vaccination in Brazil: effectiveness and health impact seven years post-introduction. Expert Rev Vaccines 2014;13(1):43-57.

³ Rha B, Tate JE, Payne DC, Cortese MM, Lopman BA, Curns AT, Parashar UD. Effectiveness and impact of rotavirus vaccines in the United States – 2006-2012. Expert Rev Vaccines 2014:13(3):365-376.

⁴ Clark A, Jit M, Andrews N, Atchison C, Edmunds WJ, Sanderson C. Evaluating the potential risks and benefits of infant rotavirus vaccination in England. Vaccine 2014 Jun 17;32(29):3604-10. doi: 10.1016/j.vaccine.2014.04.082. EPUB 2014 May 9.

Statement on Rotarix and RotaTeq vaccines and intussusception

In December 2009, WHO recommended routine immunization of infants for prevention of rotavirus disease, the most common cause of serious gastroenteritis among infants worldwide. Currently two rotavirus vaccines – Rotarix (manufactured by GSK Biologicals) and RotaTeq (manufactured by Merck & Co,. Inc.) – are available. Because a previous rotavirus vaccine (RotaShield, manufactured by Wyeth) was associated with intussusception, an uncommon form of bowel obstruction, the risk of this adverse event was specifically evaluated in pre-licensure trials of the current licensed rotavirus vaccines. In trials, each involving >70 000 participants, conducted mainly in Finland and the United States of America for RotaTeq, and in 11 countries in Latin America for Rotarix, no increased risk for intussusception was observed. Nonetheless, WHO has recommended ongoing post-marketing intussusception monitoring when these vaccines are introduced into different populations. On 6 and 13 August 2010, the Global Advisory Committee on Vaccine Safety (GACVS) reviewed by teleconference preliminary data from post-marketing studies. On 22 September 2010, the United States Food and Drug Administration approved a label change for Rotarix to advise practitioners of new data regarding intussusception.

Since 2007, the Pan American Health Organization has collaborated with Ministries of Health, the United States Centers for Disease Control and Prevention (CDC), and PATH, to evaluate, in Brazil and Mexico, the potential risk of intussusception after Rotarix immunization during routine use. Preliminary analyses of the surveillance data collected have identified a clustering of 18 hospitalizations following intussusception (none of which were associated with fatality) in the period 1 to 7 days after the first dose in Mexico, corresponding to a rate of intussusception that was about 4-5 times higher than in later periods after vaccination, after adjusting for age. No clustering was observed after the first dose in Brazil. If these findings in Mexico are confirmed, they would translate to a risk of about one to two additional intussusception hospitalizations per 100 000 vaccinees or about 20-40 additional cases per year nationwide at current vaccination rates (the Mexican birth cohort is approximately 2 million).

A similar study sponsored by GSK Biologicals in a different population in Mexico also found a possible increased risk of intussusception of about 1.7-fold in the 30-day period following the first dose, with a clustering of cases in the first week after vaccination. In Australia, post-marketing surveillance studies found no increased risk of intussusception up to 9 months of age with either Rotarix or RotaTeq vaccines, but there was the possibility of a temporal increase in intussusception in the first week after vaccination with both vaccines, although these findings are based on relatively few cases. In the United States, data from both the CDC and from an evaluation sponsored by Merck & Co,. Inc. do not show evidence of an increased risk of intussusception with RotaTeq; however, the population of children under active surveillance in the United States who have received RotaTeq, is not yet large enough to rule out the level of risk in the first week after vaccination suggested by preliminary analyses of studies of Rotarix in Mexico.

Post-marketing surveillance indicates the possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccination in some populations. If confirmed, the level of risk observed in these post-marketing studies is substantially lower than the risk of one case of intussusception in 5 000-10 000 vaccinees identified after RotaShield vaccination. The documented benefits of rotavirus vaccination against rotavirus-related disease are substantial. For example, in Mexico, nationwide use of Rotarix vaccine would prevent approximately 12 000 hospitalizations and 700 deaths from diarrhoea each year, a benefit that greatly outweighs the risk of vaccine-associated intussusception found in this preliminary analysis of possibly 20-40 cases. Furthermore, some studies have suggested that rotavirus vaccines may have an overall long-term protective effect against intussusception, an effect that might outweigh any short-term increased risk in the period shortly after the first dose of vaccine. Further data collection and analyses of information from Latin America and other surveillance systems are ongoing, and GACVS will continue to review these data as they become available.

Statement on Rotarix vaccine and DNA from porcine circovirus type 1 (PCV1)

On 25 March 2010, WHO’s Global Advisory Committee on Vaccine Safety (GACVS) met by teleconference to review new data on Rotarix, an oral vaccine for prevention of rotavirus gastroenteritis. Academic investigators recently reported to the vaccine manufacturer, GlaxoSmithKline, that the vaccine contains DNA from porcine circovirus type 1 (PCV1). PCV1 is not known to cause disease in animals or humans. Further analysis of the master cell bank and master viral seed used for vaccine production have demonstrated the presence of PCV1 DNA, which in retrospect has been in the vaccine throughout its clinical development, including the prelicensure clinical trials. There are studies underway both by the manufacturer and others that will provide additional information to help more fully assess this new finding.

The safety of Rotarix is supported by both large clinical trials prelicensure and an extensive (>60 million doses) postlicensure safety experience. GACVS reviewed the safety data from both clinical trials and spontaneous reports, both of which supported the continued safety of Rotarix. Rotavirus gastroenteritis is the most common cause of severe diarrheal disease in young children throughout the world, with an estimated 527 000 deaths annually among children under five years old. Given the extensive clinical data supporting the safety of Rotarix and the benefits of rotavirus vaccination for children, GACVS considers that the benefits of vaccination far outweigh any currently known risk associated with use of Rotarix. GACVS will continue to review data as it becomes available and will update this statement as we learn more.

Rotavirus vaccination - WHO does not recommend any change to use of Rotarix vaccine

Following announcements today by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding use of the rotavirus vaccine, Rotarix, the World Health Organization (WHO) encourages all countries using the vaccine to carefully consider the significant benefits of continued use of the vaccine in any decisions about further use.

The FDA and EMA statements follow the recent report to the vaccine manufacturer that DNA sequences originating from porcine circovirus 1 (PCV1) had been detected in two batches of the vaccine during a study undertaken in the United States of America (USA).

WHO concurs with the views of the FDA and EMA that the findings do not present a threat to public health. Moreover, rotaviruses are the most common cause of severe diarrhoeal disease in young children throughout the world, with an estimated 527 000 deaths among children under five years old, most of whom live in low-income countries. Therefore, WHO does not recommend any change to use of the vaccine. The vaccine is prequalified by WHO, and the prequalification status remains unchanged.

WHO will continue to work closely with the FDA , EMA and other regulatory agencies to evaluate further information that the manufacturer will be providing as a matter of urgency.

WHO position paper on rotavirus vaccines

Statement on RotaTeq® vaccine and intussusception

WHO and the Global Advisory Committee on Vaccine Safety (GACVS)1 have taken note of the United States Food and Drug Administration (FDA) Public Health Notification to health-care providers and consumers about reports of intussusception following the use of RotaTeq® vaccine (Rotavirus, Live, Oral, Pentavalent vaccine manufactured by Merck and Co., Inc.) in the United States of America. The reported cases were detected through routine monitoring of RotaTeq® vaccine by the United States Vaccine Adverse Event Reporting System (VAERS). It should be noted that the number of intussusception cases reported to date after RotaTeq® administration does not exceed the number of cases expected based on background rates in the United States infant population, and therefore does not suggest an increased risk of intussusception with RotaTeq®. However, continued monitoring is warranted.

GACVS has previously concluded that clinical trial data and preliminary data from adverse event reports in the post-marketing phase, from the United States of America and elsewhere, did not show an increased risk for intussusception following RotaTeq®; the current information from the United States of America does not change the previous GACVS conclusions. The Committee is in agreement with the steps taken by the FDA and the United States Centers for Disease Control and Prevention (CDC) to remind health-care providers and consumers to maintain a high level of attention to the diagnosis and reporting of intussusception in order to appropriately investigate their potential association with rotavirus vaccination. WHO and the GACVS will continue to review the data for cases of intussusception reported in the United States of America by the CDC and FDA as well as reports from other countries which have introduced rotavirus vaccine.

Safety of Rotarix and RotaTeq rotavirus vaccines

Following the withdrawal of the first licensed rotavirus vaccine (a tetravalent rhesus reassortant rotavirus vaccine, commercially known as Rotashield®) from the United States market because of its association with an incidence of intussusception among recipients of about 1 per 10 000, two newly-developed rotavirus vaccines, Rotarix™ (GSK Biologicals) and Rotateq™ (Merck Research Laboratories), have been developed and licensed for use in a number of countries. At its meetings in December 2004 and December 2005, the Global Advisory Committee on Vaccine Safety (GACVS) reviewed efficacy and safety data that were accumulating from the Phase III trials, provided to the Committee in confidence by the two companies developing the vaccines. The results from these trials have now been published and confirm the high efficacy of both vaccines against severe rotavirus diarrhoea and the absence of evidence of an increased risk of intussusception associated with either vaccine. In the trial of the Rotarix™ conducted on over 60 000 infants from 11 Latin American countries and Finland, 25 cases of definite intussusception were reported, nine in the vaccine group and 16 in the placebo group. Of these 25 cases, 13 were reported within 31 days of a vaccine (or placebo) dose, six in the vaccine group and seven in the placebo group. A further three cases in the vaccine group and nine in the placebo group were reported after this 31-day window (median duration of total safety surveillance was 100 days after the first dose). In the trial of Rotateq™ conducted on approximately 70 000 infants in 11 countries in North America, Latin America and Europe, there were 12 cases of intussusception among vaccine recipients and 15 among placebo recipients within one year of the first dose, and six and five respectively within 42 days of any dose. In neither trial was there evidence of an excess of other serious adverse effects among vaccine recipients.

In considering these findings, the Committee concluded that the pre-licensing safety profiles derived from the Phase III trials of the current vaccines were reassuring. However, the confidence intervals on the intussusception risks were wide and the Committee considered that the possibility remained of a risk of intussusception or of other adverse effects during routine use of the vaccines. Post-marketing surveillance will be key to addressing safety issues at a population level. The GACVS reiterated the importance of a commitment to post-marketing surveillance in developing countries, including those where the current capacity to conduct such studies was inadequate.

At its meeting in June 2006, the GACVS noted that WHO is developing a generic protocol for post-marketing surveillance of rotavirus vaccine safety that can be adapted at country level for implementation. This protocol includes monitoring of intussusception as well as other potential safety issues, including other gastrointestinal symptoms, the potential effect of malnutrition, and shedding and transmission of vaccine virus strains. WHO will also support the post-marketing surveillance of rotavirus vaccine safety through a network of sentinel countries.

The Committee also noted that plans are underway, under the leadership of the United States Centers for Disease Control and Prevention, to develop and make available a protocol for the post-marketing surveillance for the impact of rotavirus vaccine.

The Committee strongly recommended that introduction of rotavirus vaccines should be associated with careful consideration of post-marketing surveillance at country level and securing its funding as an essential part of immunization programmes.

References

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