Global Advisory Committee on Vaccine Safety, December 2010
The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, was established by WHO to provide independent, scientifically rigorous advice on vaccine-safety issues of potential global importance.1 GACVS held its 23rd meeting in Geneva, Switzerland, in December 2010.2 The Committee (i) reviewed new data related to the risk of intussusception after rotavirus vaccination, (ii) reviewed new data on the safety of pandemic influenza A (H1N1) 2009 vaccines, (iii) examined the experience of using yellow fever vaccines among HIV-positive people, and (iv) reviewed the experiences of 3 West African countries which are monitoring the safety of a new meningitis A conjugate vaccine.
Rotavirus vaccine and intussusception
In December 2009, WHO recommended that all infants be routinely immunized to prevent rotavirus disease, the most common cause of serious gastroenteritis among infants worldwide. Two rotavirus vaccines are available: Rotarix (manufactured by GSK Biologicals) and RotaTeq (manufactured by Merck & Co., Inc.). Because a previous rotavirus vaccine (Rotashield, manufactured by Wyeth) was associated with an increased incidence of intussusception, an uncommon form of bowel obstruction, the risk of this adverse event was specifically evaluated in prelicensure trials of the currently licensed vaccines. In trials prior to registration no increased risk of intussusception was observed: each trial involved >70 000 participants. The trials were conducted mainly in Finland and the United States of America for RotaTeq, and in 11 countries in Latin America for Rotarix. Nonetheless, WHO has recommended that postmarketing surveillance for this adverse event should continue whenever these vaccines are introduced into new populations. On 6 and 13 August 2010, GACVS reviewed (during a teleconference) the preliminary data from postmarketing studies that suggested an increased risk of intussusception associated with Rotarix in some populations. On 22 September 2010, the United States Food and Drug Administration approved a label change for Rotarix advising practitioners of the new data on intussusception,3 and WHO provided an update related to the preliminary findings from those active surveillance studies.4
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 the potential risk of intussusception after routine use of Rotarix in Brazil and Mexico. Preliminary analyses of the surveillance data have identified 18 hospitalizations following intussusception (none of which were associated with death). These occurred within 1–7 days after administration of the first dose in Mexico; after adjusting for age, this rate is about 4–5 times higher than that occurring during later periods after vaccination. No similar excess was observed after administration of the first dose in Brazil. A case-control analysis of the data from Mexico found an association similar to that in the case-only analysis. These data from Mexico correspond to a risk of about 1–2 additional hospitalizations for intussusception per 100 000 infants vaccinated, 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 an increased risk of intussusception: an approximately 1.7-fold increase during the 30 days following the first dose, with a cluster of cases occurring during the first week after vaccination.
In Australia, postmarketing surveillance studies found no increased risk of intussusception among children aged ≤9 months with either vaccine; however, the studies found a temporal increase in intussusception with both vaccines during the first week after vaccination, although these findings were based on relatively few cases. In the United States, data from both the CDC and from an evaluation sponsored by Merck & Co., Inc., did 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 during the first week after vaccination that has been suggested by preliminary analyses of Rotarix in Mexico and with both vaccines in Australia.
In summary, postmarketing surveillance indicates the possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccine in some populations. If the findings are confirmed, the level of risk observed in these studies is substantially lower than the risk of 1 case/5000–10 000 in infants who received the Rotashield vaccine. The benefits of rotavirus vaccination in preventing rotavirus gastroenteritis and its consequences are substantial. For example, in Mexico it is estimated that nationwide use of Rotarix would prevent approximately 12 000 hospitalizations and 700 deaths from diarrhoea each year, a benefit that greatly outweighs the potential risk of 20–40 cases of vaccine-associated intussusception found in these preliminary analyses. Additional data are being collected and analysed from Latin America and other areas. GACVS will continue to review these data as they become available.
Safety of pandemic influenza A(H1N1) 2009 vaccines
GACVS reviewed data on the safety of pandemic influenza A (H1N1) 2009 vaccines. Overall, safety information for the pandemic influenza vaccines continues to be reassuring. Since the Committee’s earlier report in June 2010,5 data from passive surveillance from different countries has not generated any new safety concerns other than reports of narcolepsy from Finland and Sweden in August. These reports are being investigated by independent groups in Europe. Preliminary analyses of active surveillance studies for Guillain–Barré syndrome, which have evaluated both adjuvanted and unadjuvanted vaccines, suggest that there may be a small risk associated with vaccination (1–2 cases per million doses of vaccine administered). Even if this finding is confirmed, the data suggest that the risk would be much lower than that observed following the 1976 swine influenza vaccination campaign in United States; it would be similar to the risk that has been associated in some, but not all, studies with the use of seasonal influenza vaccine (an excess risk of the order of 1–2 cases/million doses). Final analyses of active surveillance studies are expected to be completed by late 2011.
Yellow fever vaccine and HIV infection
WHO recommends that all people aged ≥9 months living or travelling in areas where there is a risk of yellow fever transmission should be vaccinated. However, the vaccine is contraindicated for people who are severely immunocompromised.6 The benefits of mass vaccination campaigns for yellow fever are recognized in endemic countries, and millions of individuals are vaccinated against the disease every year in countries where the prevalence of HIV is 1–5% among those aged 15–49 years. In many places access to laboratory testing and other resources for diagnosing and treating HIV infection is poor, and many people with undiagnosed advanced HIV infection are likely to have received the vaccine.
At its June 2008 session, GACVS recommended that in light of the significant number of doses of yellow fever vaccine being delivered (and planned to be delivered) in preventive vaccination campaigns in endemic countries, some of which have a significant prevalence of HIV infection, appropriate follow-up studies after vaccine use should be conducted to improve the data on the safety and immunogenicity of this vaccine in individuals infected with HIV.7 GACVS has reviewed the latest data from the limited published literature and the preliminary reports of experience monitoring vaccination campaigns in Africa and Latin America.
Published studies on the safety and immunogenicity of yellow fever vaccines in HIV-positive people are limited to small studies and case reports, mainly of travellers with CD4 >200 cells/mm3. With the exception of 1 case of fatal meningoencephalitis, these studies did not detect any other serious adverse events following immunization (AEFI) among HIV-positive individuals. However, little evidence has accumulated about the safety of this vaccine in people with advanced HIV infection. Data about the immune response to the vaccine are scarce but show consistent immunogenicity in HIV-positive people with CD4 counts >200 cells/mm3.
In West and Central Africa, between 2007 and 2010, 10 countries undertook vaccination campaigns against yellow fever, during which about 50 million people were vaccinated. In these countries, surveillance efforts have been implemented in collaboration with national health authorities and local expert committees. Analyses of the safety data are continuing in 7 countries, but so far around 194 serious AEFI have been reported, and more than three quarters of patients have been tested for HIV. Only a few individual cases of serious AEFI have occurred in HIV-positive individuals. Similar findings have been reported from vaccination campaigns in Latin America.
In summary, monitoring vaccination campaigns in countries where the prevalence of HIV is about 1–5% has identified only a few HIV-positive individuals among those with any serious AEFI; no clear risk has been identified that precludes the use of yellow fever vaccine in people infected with HIV. However, the sensitivity of these studies to detect serious AEFI has not been established. In addition, GACVS is awaiting data about the completeness of case investigation, the classification of serious AEFI and the HIV status of those cases.
No changes have been suggested by GACVS to WHO’s recommendation that individuals known to be severely immunocompromised should not receive yellow fever vaccine; the available data do not identify a significant problem with mass vaccination in populations where a moderate proportion of individuals are HIV-positive. However, GACVS strongly recommends that additional data on safety and immunogenicity should be obtained on the effect of vaccination in HIV-positive individuals, and especially in those with advanced HIV infection. This could be accomplished by strengthening systems for detecting and investigating serious AEFI during vaccination campaigns. Also, additional clinical studies of yellow fever vaccines administered to HIV-positive individuals should be conducted.
Meningitis A conjugate vaccine
The Committee was updated on vaccine safety data relating to the introduction of MenAfriVac vaccine collected in the 3 early-adopter countries (Burkina Faso, Mali and Niger) during September 2010. The data previously presented from 7 clinical trials from 5 sites (Gambia, Ghana, India, Mali and Senegal), involving 4614 participants, did not identify any unexpected safety issues with this lyophilized meningitis A conjugate vaccine.5 During the initial phase, 4 districts in the 3 countries were selected for vaccine introduction. Spontaneous AEFI reporting was stimulated during preparatory training activities and supported by national AEFI review committees in all 3 countries.
A total of 215 reports of AEFI, including 34 serious adverse events, were received after 1.04 million people were vaccinated. Based on a review by national expert committees, only 1 serious AEFI (an anaphylactic reaction) was classified as related to vaccination. So far, these data do not suggest that there should be any special concern about safety. However, GACVS had concerns about the completeness of ascertainment of AEFI. Data were collected largely through existing passive surveillance systems, and could not be compared to background rates of occurrence of the conditions of interest in the same populations.
Based on GACVS’s recommendations, the 3 countries have developed a modified postmarketing surveillance plan for the next phase of vaccine introduction in order to generate additional data on safety. The Committee recognized that it would not be practical to adopt a large-scale active surveillance approach and therefore recommended giving priority to enhancing existing surveillance systems. Active surveillance, focusing on selected syndromes of interest, will be conducted in sentinel sites that have adequate infrastructure.
The Committee also addressed precautions from the package insert recommending that the vaccine should not be administered during pregnancy unless there is definite risk of group A meningococcal disease, and lactating women should not be given the vaccine since it is not known whether it is excreted in breast milk. The Committee noted that this kind of precautionary statement has also been used for other inactivated vaccines, including other meningococcal conjugate vaccines, and is not based on any known risks to these groups. Given the clear benefits of the vaccine, the increased risk of disease in the geographical area and past experiences using similar vaccines in comparable conditions, GACVS supported WHO’s technical guidance that MenAfriVac should be offered to pregnant and lactating women residing in the meningitis belt during any stage of pregnancy or lactation. A plan should be developed to follow up vaccinated pregnant women in antenatal or obstetric clinics, and to monitor pregnancy outcomes by making appropriate comparisons with unvaccinated pregnant women.
GACVS highlighted the importance of developing a robust postmarketing surveillance plan for any new vaccine before it is introduced. Furthermore, GACVS emphasized the importance of considering whether to conduct studies in specific groups during the product development stage, especially those groups which may be at higher risk of disease from vaccination.
GACVS concluded that the data for MenAfriVac vaccine had identified no safety concerns regarding the use of this vaccine. However, GACVS emphasized the need for additional effective postmarketing surveillance to provide more complete information about the safety profile of the vaccine, including its effects in specific groups, especially pregnant women.
- See No. 41, 1999, pp. 337–338.
- GACVS invited additional experts to discuss evidence related to particular topics. These experts included people affiliated with the Therapeutic Goods Administration in Woden, Australia and the United States Centers for Disease Control and Prevention in Atlanta, GA, USA, on rotavirus vaccines; the Ministry of Health in Beijing, China, and University of Laval in Quebec, Canada, about pandemic influenza vaccines; and the Ministry of Health, Ouagadougou, Burkina Faso, on conjugate meningococcal A vaccine.
- Information on Rotarix: labeling revision pertaining to intussusception. Washington, DC, United States Food and Drug Administration, 2010 (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm226690.htm, accessed December 2010).
- Statement on Rotarix and Rotateq vaccines and intussusception. Geneva, World Health Organization, 2010 (http://www.who.int/vaccine_safety/topics/rotavirus/rotarix_and_rotateq/intussusception_sep2010/en/index.html; accessed January 2011).
- See No. 30, 2010, pp. 285–291.
- See No. 40, 2003, pp. 349–359.
- See No. 32, 2008, pp. 287–292.