Global Advisory Committee on Vaccine Safety, report of meeting held 12-13 June 2013
The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, was established by WHO to provide independent scientifically rigourous advice on vaccine safety issues of potential global importance.1 GACVS held its 28th meeting in Geneva, Switzerland, on 12–13 June 2013.2The Committee reviewed 7 specific issues:
- the experience of 4 Asian countries with the use of Hib-containing pentavalent vaccine;
- the safety profile of varicella vaccines;
- the safety of immunization during pregnancy;
- the monitoring of yellow fever vaccine safety during mass vaccination campaigns in Africa;
- the safety profile of Japanese encephalitis vaccines;
- updates on the risk of narcolepsy related to the use of the pandemic influenza vaccine Pandemrix®;
- recent data from the post-licensure monitoring of human papillomavirus vaccines.
Pentavalent vaccine in Asian countries
Since 2008, Haemophilus influenzae type b(Hib) vaccine has been introduced progressively into Asian countries’ immunization programmes. Hib vaccine has usually been introduced as a component of a combination pentavalent vaccine, which has replaced the traditional diphtheria–tetanus–whole-cell pertussis (DTwP) or DTPwP-hepatitis B vaccines. As with the introduction of any new vaccine, there has been particular attention to adverse events following immunization (AEFI), which presented challenges in several countries in the WHO South-East Asia and Western Pacific Regions. Four countries that introduced pentavalent vaccines from 3 different manufacturers presented their experience:
(1) Sri Lanka introduced the pentavalent vaccine from Crucell in January 2008. Within 3 months, 4 reports of deaths and 24 reports of suspected hypotonic-hyporesponsive episodes prompted regulatory attention and precautionary suspension of the initial vaccine lot. A subsequent death that occurred with the next lot in April 2009 led the authorities to suspend pentavalent vaccine use and resume DTwP and hepatitis B vaccination.
(2) Bhutan introduced pentavalent vaccine from Panacea in September 2009. The identification of 5 cases with encephalopathy and/or meningoencephalitis shortly after pentavalent vaccination prompted the authorities to suspend vaccination on 23 October 2009. Subsequently, 4 additional serious cases related to vaccine administered prior to suspension were identified and investigated.
(3) India introduced pentavalent vaccine from the Serum Institute of India in the states of Tamil Nadu and Kerala in December 2011. This was followed by expansion of vaccine usage in the states of Goa, Pondicherry, Karnataka, Haryana, Jammu and Kashmir, Gujarat and Delhi during the second half of 2012 through the first quarter of 2013. To date, 83 AEFI cases, some of which were associated with mortality, have been reported after vaccine introduction from some states.
(4) Vietnam introduced pentavalent vaccine from Crucell in June 2010. Through May 2013, a total of 43 serious AEFI cases were investigated, including 27 with a fatal outcome. Following receipt of reports of 9 deaths following vaccination between December 2012 and March 2013, health authorities suspended use of the vaccine.
In each country the serious AEFIs were reviewed with independent national and international experts. Based on those reviews, none of the fatal cases could be classified as having a consistent causal association with immunization. In Sri Lanka, after a comprehensive investigation and review, the same pentavalent vaccine product was re-introduced in 2010. Since then and up to 2012, another 14 deaths were reported among infants who had received the Crucell pentavalent vaccine. In addition, 6 of 19 infant deaths were found at autopsy to have severe congenital heart disease. Following this finding, in Sri Lanka children with known severe congenital heart disease are now vaccinated under close medical supervision, and no additional deaths among children have since been reported in temporal association with pentavalent vaccine administration. In Bhutan, following a similar investigative process, the vaccine was reintroduced in 2011. Vietnam is currently reviewing clinical, epidemiological and vaccine quality issues. The 3 countries that suspended vaccine use also actively managed public communication about the observed events and their public health implications.
GACVS identified several common features among the countries that experienced significant vaccine safety concerns following pentavalent vaccine introduction. In all countries, the vaccination programme is well established and achieves high coverage (India introduced the vaccine in states with high vaccine coverage). Vaccine introduction was also accompanied by very thorough training of health-care staff about the benefits and risks of the vaccine. In Sri Lanka and Bhutan, discontinuation and resumption of pentavalent vaccine use did not significantly modify the pattern of serious AEFI reports following substitution of previously utilized vaccines. In addition, several limitations were noted in all 4 countries. Incomplete clinical information significantly complicated the causality assessment. For some cases, additional clinical information allowed another cause of death to be identified. For other cases, there remained insufficient clinical information to allow the cause of death to be ascertained, making it impossible to rule out sudden infant death syndrome (SIDS).
The diagnosis of SIDS requires clinical information and a thorough post-mortem examination (as described in the Brighton Collaboration case definition) that is not available in many settings. As peak incidence of SIDS occurs in early infancy, a close temporal relationship between SIDS and receipt of pentavalent vaccine is expected by simple chance. GACVS emphasized the need for thorough investigation of any reported serious AEFI and the importance of establishing standard investigation procedures. In the case of SIDS in particular, the possibility of conducting autopsies, or at least investigating and rapidly documenting the circumstances of death and collecting specimens and other clinical evidence, was highlighted.
New vaccine introductions associated with increased reports of deaths and other serious AEFI present a challenge to immunization programmes with respect to their ability to properly assess, manage and communicate about serious vaccine safety concerns. Identification of serious AEFI, including death, is to be expected in a temporal relationship with any infant vaccine even if no adverse events are causally associated with the vaccine.
The findings of investigations and expert review of deaths following pentavalent vaccine in the 4 countries are reassuring although not all cases could be fully assessed due to incomplete case information. The importance of thorough clinical investigation of AEFI (e.g. lumbar puncture and cerebro-spinal fluid examination for patients with suspected meningoencephalitis), and of adequate evaluation of deaths following vaccination including autopsy to identify underlying conditions and any potential alternative causes of death, was demonstrated by the experience of those countries.
In the context of evaluating a safety signal, it is important that countries understand their own infant mortality rates and underlying causes. If a particular serious AEFI is identified as a concern, additional epidemiological studies should be conducted to ascertain factors that can be used to evaluate the evidence for risk hypotheses. SIDS, among other causes of infant mortality, would benefit from detailed epidemiological studies. This is particularly important when new vaccines such as those against Hib, pneumococcus and rotavirus are introduced in resource-poor countries and where there is increasing attention to safety concerns. GACVS also emphasized the fact that in a context of decreasing risk related to the diseases prevented by vaccines and increasing attention to AEFI, the capacity of countries that introduce new vaccines to rapidly assess and communicate using a risk communication approach should be reviewed and enhanced accordingly.
In conclusion, pentavalent vaccine introduction in Asian countries has illustrated how legitimate increased attention to AEFI can pose new challenges to national decision-makers. The review of the experience of 4 countries, their willingness to openly discuss all case information with external experts, the consistent causality assessment conclusions reached in the countries, and the carefully managed reintroduction of pentavalent vaccines in Sri Lanka and Bhutan are valuable examples of the successful maturation of national vaccine safety systems. Pentavalent vaccines provide great public health benefits that accrue from the ability to protect against 5 major threats to health in a single injection. Currently, pentavalent vaccines from 5 different manufacturers re prequalified by WHO and considered to be safe, effective and of assured quality.
Zoster vaccine safety and varicella vaccine safety in immunocompromised populations
Zoster vaccine safety
In a follow-up to the December 2012 GACVS meeting at which a general summary of varicella vaccine safety was presented, experts from the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) presented systematic post-licensure safety reviews of the zoster vaccine (Zostavax®) and safety of varicella vaccine in immunocompromised populations. The FDA completed a 7-year safety update of Zostavax® by summarizing key post-licensure observational studies conducted by CDC and Merck, a literature review from the date of licensure (May 2006) through February 2013, and analysis of reports from the Vaccine Adverse Event Reporting System (VAERS) from May 2006 through February 2013. The CDC Vaccine Safety Datalink study on Zostavax®, together with 3 post-licensure studies conducted by Merck as FDA regulatory commitments, included a total of >190 000 vaccinated study subjects. No new safety signals were identified in these studies. More than 12 000 reports were submitted globally for Zostavax® to VAERS from May 2006 through February 2013, of which 1057 were considered serious. The 3 most frequent terms for serious adverse events were herpes zoster, pain, and rash. FDA data mining using disproportionate analysis revealed adverse events predominantly associated with vaccine failure (i.e. herpes zoster despite vaccination), as well as accidental exposure and inappropriate vaccine administration (i.e. use of Zostavax® in subjects younger than the FDA approved age of ≥50 years). In summary, although safety data on the subpopulation of individuals aged ≥80 remains limited, no new safety risks have been identified or confirmed since initial licensure.
Safety of varicella vaccine in immunocompromised populations
Because diseases caused by wild type VZV are more severe and fatal in persons with defects in cell-mediated immunity, varicella vaccine has been studied for safety and efficacy in select immunocompromised populations. Studies of the safety and effectiveness of varicella vaccines were conducted in children with cancer, HIV, and post-organ transplant. All but one of the studies was conducted in developed countries. Compared to healthy children, varicella vaccine is associated with a higher risk of adverse reactions, some severe, in selected subpopulations of children with deficiencies in cell-mediated immunity. Varicella vaccine is contraindicated or should be used with caution, under strict protocol, in persons with leukaemia. Two doses of varicella vaccine are effective and safe in preventing varicella in children with HIV with CD4 T-cell count ≥15%. Case reports were identified describing other immunocompromised children primarily due to natural killer T-cell deficiency discovered after vaccination. In countries with routine childhood varicella vaccination programmes, children are likely to be vaccinated without knowledge of their immune deficiency states. The size of this group will depend largely on the prevalence of undetected and untreated HIV infection. This fact is an important consideration in introducing varicella vaccination, but should be balanced against the benefits of reducing more severe wild-type varicella disease in this subpopulation.
Immunization during pregnancy
Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. Maternal immunization can protect the mother directly against vaccine-preventable infections, and provide a cocooning effect that can potentially protect the fetus. It can also provide further direct fetal/infant protection against infection via the transport of specific antibodies to the fetus prior to birth.
At its meeting in December 2011, the Strategic Advisory Group of Experts (SAGE) asked GACVS to provide support to the review of current evidence on the safety of vaccinations in pregnant and lactating women. This request related to uncertainties about the safety of vaccination – whether intended or inadvertent – of pregnant women during mass vaccination campaigns. Such evidence would be particularly important in situations where manufacturers do not recommend the vaccination of pregnant women on precautionary grounds.
Given the broad spectrum of vaccines currently available, GACVS prioritized vaccines for review based on 2 key criteria: their potential to reduce morbidity for the pregnant woman and her fetus; and their use (or projected use) in vaccination campaign settings, which have the potential for inadvertent vaccination of pregnant women. GACVS evaluated relevant data from interventional and non-interventional studies and spontaneous reporting systems on the safety of immunization of pregnant women for several viral, bacterial inactivated vaccines, toxoid and live attenuated vaccines.
Based on the reviewed data, GACVS concluded that there is no evidence of adverse pregnancy outcomes from the vaccination of pregnant women with inactivated virus, bacterial, or toxoid vaccine. Therefore, pregnancy should not preclude women from immunization with the assessed vaccines if medically indicated.
Live vaccines may pose a theoretical risk to the fetus. However, there is substantial literature available describing the safety of live attenuated vaccines including monovalent rubella vaccines, combined measlesmumps-rubella vaccines, and oral polio vaccines. No significant adverse effects to the fetus following these live attenuated vaccines have been reported. Thus, the contraindication of measles-mumps-rubella (MMR)-containing vaccines is considered a purely precautionary measure. Inadvertent vaccination of pregnant women with MMR-containing vaccines is not considered an indication for pregnancy termination.
The benefits of vaccinating pregnant women generally outweigh the potential risks of exposure to a particular infection to the mother or her fetus/newborn if the vaccine is unlikely to cause harm. The use of selected vaccines in pregnancy is an important aspect of prenatal care, which not only improves maternal health but also benefits the neonate.
Yellow fever vaccine safety during mass immunization campaign in sub-Saharan Africa
The introduction of the yellow fever 17D vaccine in the 1930s provided an effective preventive measure resulting in a significant decline of the disease. However, there has been a resurgence of yellow fever resulting from changes in population dynamics, urbanization, deforestation coupled with other agricultural and developmental activities, climate changes and a decline in population immunity. In 2006, the Yellow Fever Initiative led by the WHO in partnership with UNICEF and GAVI was launched to control this resurgence in order to reduce the risk of epidemics in sub-Saharan Africa. This entailed a mass preventive vaccination campaign against the backdrop of other WHO-UNICEF yellow fever control strategies.
The recent (2007–2010) preventive yellow fever (YF) vaccination campaigns in West and Central African countries provided an opportunity for surveillance of AEFIs, thus further characterizing the safety of the vaccine. Nine countries were involved – Benin, Burkina Faso, Cameroun, Guinea, Liberia, Mali, Senegal, Sierra Leone and Togo. GACVS reviewed the recently published findings of surveillance of AEFIs conducted during those campaigns. In all, 38 million doses of the vaccine were administered, and 3116 AEFIs were observed (2952 non-serious and 164 serious). Of the serious AEFIs, 22 were classified as related to the YF vaccine and 142 were not related; of the 22, 6 clinical cases resembled acute neurotropic disease (YEL-AND), 5 clinical cases resembled acute viscerotropic disease (YEL AVD) and a further 11 involved hypersensitivity reactions. The attack rates per 100 000 vaccinated people obtained from the study therefore were 0.016, 0.013 and 0.029 for YEL-AND, YEL-AVD and hypersensitivity reactions respectively. These rates were lower than those seen with recipients of a first dose of YF vaccine in more developed settings. The median time to onset (days) was observed as 8 (YEL-AND), 4 (YEL-AVD) and 1.8 (hypersensitivity reactions). Vaccine virus identification, however, was not successful for acute cases.
The authors noted the challenges and limitations of the study to account for a relatively low specificity and sensitivity of active case findings due to many coincidental cases, operational issues with inadequate collection, storage and transportation of specimens, poor laboratory and investigation facilities, cultural practices hindering post-mortem examination, misclassification of cases, and inadequate prioritization of pharmacovigilance, amongst others. Despite the limitations, the authors concluded that the study has had impact on the countries in ensuring a proactive surveillance system as well as reinforcing the safety profile of YF vaccine in this particular setting.
GACVS noted the enormous challenges of conducting a pharmacovigilance study in a resource-limited setting. The committee suggested that enhanced vaccine safety monitoring, including additional resources to provide adequate capacity and expertise, should be included in planning vaccination campaigns. It observed that the criteria for case definition were very strict and difficult to apply appropriately in such settings. It therefore suggested that more operational criteria could be proposed that would be adapted to local clinical practice or that additional dedicated efforts be conducted to meet existing criteria. There is also a need to put standard operating procedures or tiered instructions in place to strengthen pharmacovigilance and address technical and logistic issues. GACVS also recommended that clinical and laboratory findings even if limited be more systematically correlated with post-mortem examinations.
Safety profile of Japanese encephalitis vaccines
GACVS considered recent data on the safety profiles of a cell culture based on live attenuated and 2 inactivated Japanese encephalitis (JE) vaccines. The live attenuated SA 14-14-2 JE vaccine manufactured by the Chengdu Institute of Biological Products was licensed 25 years ago and is now in routine use in several countries including China, where it is given routinely at 8 months and 2 years. Worldwide, >400 million doses of the vaccine have been administered. GACVS previously reviewed this vaccine and found it to be generally safe. The Committee recommended studies in special populations, on viraemia, and post-marketing surveillance.3Subsequently, studies on a few hundred children in the Philippines and Sri Lanka examined the safety of the SA-14-14-2 and found that the vaccine produces only mild local and systemic reactions. A study in India on 19 adults previously unexposed to Japanese encephalitis found no evidence of viraemia up to 2 weeks after SA-14-14-2 administration.
Post-marketing surveillance carried out by the Chinese Centre for Drug Evaluation during 2009–2012 reported 6024 AEFI of which 70 were considered severe. The severe events included a range of disorders including febrile convulsions, thrombocytopenic purpura and encephalitic/meningitic illness. Of the 9 encephalitis cases, one was considered vaccine related while the others were classified as coincidental illnesses. There were 4 recorded deaths, none of which were considered related to vaccination on expert review. The GACVS reviewed these data and noted that although there was no evidence of a safety signal, the number of events recorded in the AEFI reporting system was low given that >70 million doses of vaccine have been administered.
Limited data demonstrating safety in HIV-infected individuals were available for the inactivated mouse-brain vaccine, which was marketed as either Biken® or JE-Vax®. The production and distribution of this vaccine has ceased, and the last lots of the vaccine expired in May 2011. GAVCS recommended that studies in immunocompromised populations, particularly individuals with HIV, should be carried out with the new inactivated vaccines, starting with those with CD4 T-cell counts >200. Additional data on the recently licensed inactivated vaccines, Ixiaro®, made by Intercell SA, and Jeev®, made by Biological E Ltd, in India were presented by the manufacturers. inactivation of the SA 14-14-2 strain. Both vaccines were licensed on the basis of serologic correlates and have not been evaluated against disease. Ixiaro® was evaluated in 1869 children from 2 months to 18 years in a Phase III trial in the Philippines, a JE-endemic area. Study participants received either full (6 μg) or half (3 μg) doses of Ixiaro® (2 doses 1 month apart), Havrix® hepatitis A vaccine for children > 1year or Prevnar® 7-valent pneumococcal conjugate vaccine for children aged <1 year. The safety profile was generally comparable with the age-specific control vaccines. In children aged <1 year, the dominant local reaction was redness; in the older ages pain and tenderness were most common. The predominant systemic reaction was fever, mostly ≤39.3 °C. Immunogenicity and safety of Ixiaro® compared to JenceVac® (a mouse brain inactivated vaccine made by Korean Green Cross) were investigated in 60 healthy Indian children aged 1 to 3 years. No difference was seen in the safety profiles of these vaccines.
Overall, GAVCS noted that the live attenuated and the inactivated vaccines based on SA-14-14-2 appear to have an excellent safety profiles. The Committee emphasized the need for building post-marketing surveillance systems in countries where disease is endemic and vaccines are used, and currently only limited data are collected post-licensure. GACVS recommended more detailed study of the safety profile of those vaccines in pregnant women, on viral shedding of the live vaccine, and the implications for the efficacy and safety of the vaccine in infants with high maternal antibodies against JE virus.
Update on human papillomavirus vaccines
The Committee reviewed updated information about the safety of human papillomavirus vaccines (HPV) vaccines. The last review was conducted in June 2009,4and GACVS noted at the time that accumulating evidence on the safety of HPV vaccines was reassuring and that studies on HPV immunization had been initiated, along with capacity-building for adverse events monitoring. GACVS continues to place a high priority on the ongoing collection of high-quality safety data in settings where the vaccine is being introduced.
In the past 4 years, safety data continued to accumulate as countries have initiated or expanded their immunization programmes. The GAVI Alliance has also begun taking steps to make HPV vaccine available to women in developing countries where the burden of cervical cancer is considerable. To date, some 175 million doses of HPV vaccines have been distributed. A review of adverse events reported to the US Vaccine Adverse Event Reporting System following the distribution of >23 million doses was published in 2009.5Both manufacturers have developed pregnancy registries and are maintaining long term safety studies in conjunction with efficacy.
The Committee reviewed data from the United States, Australia, Japan and the manufacturers of Cervarix® (GlaxoSmithKline) and Gardasil® (Merck). Updates from the United States included an extension of the spontaneous reports to VAERS since the published review in 2009 as well as completed and planned studies from the Vaccine Safety Datalink. In Australia, a new programme targeting males started in February 2013 and data are starting to become available. Data from all sources continue to be reassuring about the safety of both vaccines.
The data from VAERS now includes >50 million doses distributed and the profile has not changed since the review in 2009. Reported adverse events not identified at the time of the first review, namely syncope and venous thromboembolism (VTE), were further investigated. Syncope continues to be reported but remains an event with a plausible relationship given the population and settings in which HPV vaccine is used. Adherence to a 15-minute observation period following vaccination has thus been strengthened as a recommendation. For VTE, while a rapid cycle analysis in the VSD did not find an increased risk, this is being further investigated with appropriate control for confounders such as oral contraceptive use, smoking and other risk factors in this population. Similarly, the VSD did not find any increased risk of Guillain-Barré syndrome or stroke. In Australia, safety surveillance has been enhanced and an expert group evaluated early reported events, including a signal regarding anaphylaxis. To date, with almost 7 million doses distributed, the previously investigated concern of increased anaphylaxis was not confirmed. Following the extension of the vaccination programme in males and enhanced surveillance since 1 February 2013, preliminary results show the safety profile of Gardasil® to be similar to the profile among females. Finally, there have been no further concerns regarding demyelinating disease or other chronic conditions also investigated earlier by the expert group.
Surveillance from the 2 manufacturers found no signals suggesting any necessary revisions to product labelling. Both have maintained surveillance of pregnancy outcomes following inadvertent vaccination during pregnancy. Detailed analyses of results have not found any new adverse outcomes related to HPV vaccination. For Gardasil®, long term follow-up has now extended to >8 years in the longest cohort, and no significant increase in newly diagnosed health events have been identified among those vaccinees. Updated analyses of the pregnancy registry have also been reassuring in that no adverse pregnancy outcomes have been observed beyond background expected rates. For Cervarix®, the data have been similarly reassuring regarding pregnancy outcomes and specific events of interest such as immune mediated diseases. Risk of syncope and anaphylaxis have been added to the label to warn of these potential events, the former being also possibly related to conditions around the vaccination experience itself.
Cases initially resembling complex regional pain syndrome (CPRS) were reported from Japan where >8 million doses of HPV vaccines have been distributed. CPRS is a painful condition that emerges in a limb usually following trauma. Cases have been reported following injury or surgical procedures. It remains of unknown etiology and may occur in the absence of any documented injury. CPRS following HPV vaccines has received media attention in Japan and the number of reported cases has risen to 24, only 7 of which were reported through usual post-marketing surveillance channels. Review by an expert advisory committee could not ascertain a causal relationship to vaccination given lack of sufficient case information and inability to reach a definitive diagnosis in many cases. While these are under investigation, Japan has continued to provide HPV vaccine in their national programme.
In summary, 4 years after the last review of HPV vaccine safety and with >175 million doses distributed worldwide and more countries offering the vaccine through national immunization programmes, the Committee continues to be reassured by the safety profile of the available products. Anaphylaxis and syncope, outcomes previously identified as concerns, have been addressed through further studies and appropriate revisions were made to the product labelling. Serious adverse events that have been reported as potential signals have been investigated in more detail, including Guillain-Barré syndrome, seizures, stroke, venous thromboembolism, anaphylaxis, and other allergic reactions – many using rapid cycle analysis in the VSD in the United States. Surveillance of pregnancy outcomes among women inadvertently vaccinated during pregnancy through spontaneous reports and registries have not detected any adverse outcomes above expected rates.
The cases of chronic pain being reported from Japan deserve specific mention. To date there is little reason to suspect the HPV vaccine, given its growing use worldwide, in the absence of a similar signal from elsewhere. Recognizing the public concerns voiced, the Committee urges careful documentation of each case and a thorough search for a definitive diagnosis by medical specialists in order to best guide treatment. A timely clinical assessment and diagnosis of each case followed by appropriate treatment is therefore essential.
Update on pandemic influenza vaccine (Pandemrix®) and narcolepsy
The Committee has previously reviewed data from studies on the use of the pandemic influenza vaccine (monovalent A(H1N1)pdm09 vaccine) in Finland, Sweden, Ireland, the UK and France which all demonstrated an increased risk of narcolepsy following Pandemrix® vaccination in children and adolescents. The studies in Sweden and France also found evidence of an increased risk in adults. The Committee reviewed newly available data from Finland about the safety of Pandemrix® vaccine in adults. The retrospective cohort study linked vaccination data of the whole adult population to incident cases of narcolepsy identified through the national care register during the follow-up period from 1 January 2009 to 31 December 2011. The comparison of incidence rates indicated a 3–5-fold (after sensitivity analysis 2–4-fold) risk of narcolepsy among vaccinated compared to unvaccinated adults. The increased risk was seen 8 months post vaccination; thereafter, no increased risk was observed. The reports from Sweden, France and Finland concur that young adults have an increased risk of narcolepsy after Pandemrix® vaccination. GACVS acknowledges this finding suggesting a possible risk of narcolepsy among adults, although it remains lower than that seen among children. Further follow-up research is required to confirm the strength of the observed association and size of the risk. Because of the continued threat of emergence of new pandemics and the expected need for new pandemic vaccines, the Committee reiterated the urgency of continued research to identify the underlying biological mechanisms of this association.
- See No. 41, 1999, pp. 337–338.
- GACVS invited additional experts to present and discuss evidence related to particular topics. These experts included persons affiliated with: Bio-Manguinhos, Rio de Janeiro, Brazil; Center for Biologics Evaluation and Research (U.S. F.D.A), Rockville MD, USA; Centers for Disease Control and Prevention, Atlanta GA, USA; Center for Drug Evaluation of China; Chengdu Institute of Biological Products, Chengdu, China; Crucell Holland, Leiden, The Netherlands; GlaxoSmithKline Biological, Wavre, Belgium; Intercell, Vienna, Austria; Merck & Co, Upper Gwynedd PA, USA; Ministry of Health and Family Welfare, India; National Centre for Disease Control, Canberra, Australia; National Institute of Hygiene and Epidemiology, Hanoi, Viet Nam; University of Medical Sciences of Bhutan.
- See No. 4, 2008, pp. 37–44.
- See No. 5, 2009, pp. 30–36.
- Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA, 2009, 302(7):750-757. [doi: 10.1001/jama.2009.1201]