Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 17-18 December 2008

Published in the WHO Weekly Epidemiological Record on 30 January 2009

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, was established by WHO to deal with vaccine-safety issues of potential global importance independently from WHO and with scientific rigour.1 GACVS held its nineteenth meeting in Geneva, Switzerland, during 17–18 December 2008.2 The Committee reviewed the safety profiles of rotavirus vaccines and human papillomavirus (HPV) vaccines, discussed several vaccine safety alerts in immunization programmes supported by WHO and reviewed the progress of its subgroups.

Safety of rotavirus vaccines

The Committee had previously reviewed the safety of Rotateq and Rotarix vaccines, mainly in the context of data gathered from large-scale clinical trials set up before both vaccines had been registered. The results of these trials had been reassuring in terms of providing information indicating that any risk of intussusception associated with either of the 2 new vaccines was lower than the level that had been associated with the (withdrawn) Rotashield vaccine. It was recognized that as the new vaccines were used in public health programmes, and as larger numbers of infants were vaccinated, it would be possible to get better estimates of any risk of intussusception or other adverse effects associated with either vaccine. The Committee has previously emphasized the importance of such studies.

At the meeting, the Committee was presented with post-marketing information on the rotavirus vaccines from each of the 2 manufacturers, from the Immunization Safety Office of the United States Centers for Disease Control and Prevention using data from the Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink (VSD) surveillance systems, from the Australian National Immunization Program and from the PAHO Network for Rotavirus Vaccines.

Surveillance data from the manufacturer of Rotateq from several ongoing studies did not indicate an increased risk of intussusception following vaccination compared with background rates, but these studies were relatively small and the confidence intervals of the possible risk were wide.

Data from 2 years of experience in VAERS with the use of Rotateq in the United States were presented. During this time, 267 cases of intussusception had been reported among recipients of >14 million doses of vaccine distributed. Analyses of these data did not identify signals indicative of an increased risk of intussusception associated with Rotateq, but use of VSD would provide a better assessment. In VSD, analysis of 5 cases of intussusception (only 2 of which were validated after medical record review) among recipients of 205 000 doses of Rotateq did not indicate an increased risk of intussception and enabled a risk of the level of 1/25 000 doses to be ruled out with reasonable confidence (a risk about 10-fold lower than that associated with Rotashield).

Data from 2 years of experience in VAERS with the use of Rotateq in the United States were presented. During this time, 267 cases of intussusception had been reported among recipients of >14 million doses of vaccine distributed. Analyses of these data did not identify signals indicative of an increased risk of intussusception associated with Rotateq, but use of VSD would provide a better assessment. In VSD, analysis of 5 cases of intussusception (only 2 of which were validated after medical record review) among recipients of 205 000 doses of Rotateq did not indicate an increased risk of intussception and enabled a risk of the level of 1/25 000 doses to be ruled out with reasonable confidence (a risk about 10-fold lower than that associated with Rotashield).

Data from the manufacturer on cases of intussusception following vaccination with Rotarix indicated that about 32 million doses of Rotarix had been distributed, predominantly in several Latin American countries. A total of 161 cases of intussusception had been reported following vaccination, 106 within 30 days of vaccination. Crude analysis indicated that the measured incidence rates were generally below background rates of disease incidence, but these data were difficult to interpret because of the likely high level of underreporting and some possible delays in the use of distributed doses. More detailed prospective studies are ongoing in Mexico and are due to start in the United States.

The Committee was also informed of ongoing studies to assess the safety of Rotarix in healthy infants, HIV-infected infants and pre-term infants in Africa, and noted the encouraging early findings of these studies with respect to both efficacy and safety.

In Australia, rotavirus vaccines had been introduced for the indigenous population in October 2006 and nationally in July 2007. Different vaccines had been chosen by different states. Data on cases of intussusception are being ascertained through a national passive reporting system, and enhanced surveillance is being undertaken in 4 sentinel sites. The Committee was presented with preliminary data indicating that a small number of cases of intussusception had been observed in infants who had received a rotavirus vaccine and that there appeared to be some clustering in the first 10 days following vaccination. However, a reporting bias could not be excluded and it was not yet clear whether the number of cases was raised above background rates; detailed analysis was pending the acquisition of further data.

The Committee was encouraged by the description of the surveillance network being developed in some Latin American countries, with facilitation by PAHO. No clear signals of vaccine-related adverse effects were yet apparent, but further strengthening of the surveillance network is a priority. These studies were also serving to accumulate data on the background natural frequency of intussusception among infants. From the above-mentioned reports, the Committee was reassured that an intussusception risk of the order of that which had been associated with Rotashield could be ruled out with confidence, but the available post-marketing surveillance data were still too few to rule out, with confidence, a risk of substantially lower magnitude. The Committee emphasized the importance of continuing to accumulate post-marketing surveillance data on intussusception and other possible adverse effects and stressed particularly the importance of setting up surveillance systems for such effects as the vaccines were introduced into increasing numbers of developing countries.

Safety of human papillomavirus vaccines

The Committee reviewed the latest SAGE recommendations on HPV vaccines as well as data related to their large-scale use as well as publications on early post-marketing surveillance. The post-licensure data from the United States regarding one HPV vaccine (Gardasil) were reassuring; the safety profile was similar to that found in the pre-licensure trials. No evidence of previously undetected serious adverse events had been found that were causally related with use of this vaccine. Of the several new scientific articles on the use of HPV vaccines published since the GACVS meeting in June 2007,3 3 focused on safety findings with observations on syncope, hypersensitivity, anaphylaxis and central demyelinating diseases. Of note was the finding of a study by Brotherton and colleagues4 conducted in New South Wales, Australia following the introduction of Gardasil. They reported 7 cases of anaphylaxis occurring within 30 minutes of vaccination during the administration of 269 000 doses of the vaccine. This rate was significantly higher than had been observed in a comparable school-based programme with meningococcal C vaccination. However, there were no serious sequelae following appropriate management. After careful methodological review, neither this report nor the other reports raised sufficient concern to change previous advice given by GACVS. In particular, there was no convincing evidence in the publication purporting an association between HPV vaccination and central demyelinating diseases.5 While allergic reactions and syncope can occur after injection with HPV vaccine, usual safety precautions should suffice.

As many countries have only recently introduced HPV vaccines at the national level, and as plans exist to introduce the vaccines in numerous countries with varying capabilities for monitoring of adverse events following immunization (AEFI), the Committee calls for increased attention to building capacity for post-marketing surveillance in those countries where introduction is being planned. The Committee also agreed to update comprehensively the review of post-marketing safety profile of HPV vaccines at its June 2009 meeting.

Vaccine safety alerts

A brief description of recent safety alerts following vaccination was presented. These included reports of 3 clusters of deaths following administration of 2 measles-containing vaccine products in India; a cluster of deaths following administration of pentavalent DTP-HepB-Hib6 vaccine in Sri Lanka; an isolated death following administration of DTP, HepB and oral poliovirus vaccine in the Lao People’s Democratic Republic; and a cluster of AEFI with a combined measles–rubella vaccine, including 1 death in the Ukraine. There is a paucity of information concerning the outcomes of 2 of the 3 investigations conducted in India, and delays or incompleteness in addressing safety issues associated with the mass immunization campaign in the Ukraine. In no instance could evidence of safety issues with the vaccine products be demonstrated. However, failure to capture relevant information and to respond to requests for additional work-up, as well as decision-making not supported by evidence, limit capacity to reach an unequivocal judgement on potential underlying causes of the events. Improved capacity for investigation and analysis, as well as clear communication regarding risks of immunization, is critical to avoid unnecessary and harmful disruption of immunization programmes. GACVS recommends that countries review their capacity to respond to vaccine safety issues and their strategies in addressing risks associated with immunization. Finally, GACVS had recently responded to the publication of a scientific article that had suggested a possible association between the use of one particular hepatitis B vaccine product and the delayed occurrence of multiple sclerosis. The details of a GACVS assessment of those findings, which in the view of the Committee did not provide convincing evidence of an association of the vaccine with multiple sclerosis, can be found on the GACVS web site.7

GACVS subgroups

There are 4 GACVS subgroups. Each subgroup has the mandate to further knowledge in its respective area. The subgroup on immune deficiencies has developed an agenda for systematically reviewing published data on vaccine adverse events for primary and acquired immune deficiencies. The subgroup on global monitoring of AEFI provides guidance to the WHO Secretariat on optimal ways to improve monitoring of AEFI at the global level, with particular reference to low-income and middle-income countries. The subgroup on safety of vaccine components is considering how to create a vaccine excipient database and how to address scientifically concerns involving non-immunogenic vaccine components. Finally, the subgroup on influenza vaccines safety reviews the available evidence about reactions to various seasonal and pandemic influenza vaccines. The findings from these subgroups are regularly discussed with GACVS and will be reported upon once consideration of a specific topic or subtopic has been completed.

  • See No. 41, 1999, pp. 337–338.
  • GACVS invited additional experts to present evidence with respect to the safety of rotavirus vaccines and human papillomavirus vaccines. Depending on the session, these experts were affiliated with the University of Melbourne Royal Children’s Hospital in Australia; the United States Centers for Disease Control and Prevention in Atlanta, GA, USA; RTI International in Atlanta, GA, USA; Merck Research Laboratories in West Point, PA; and GlaxoSmithKline Biologicals in Rixensart, Belgium.
  • See No. 28/29, 2007, pp. 255–256.
  • Brotherton JML et al. Anaphylaxis following quadrivalent human papillomavirus vaccination. Canadian Medical Association Journal, 2008, 179:525–533.
  • Sutton I et al. CNS demyelination and quadrivalent HPV vaccination. Multiple Sclerosis, 19 September 2008. [e-publication ahead of print].
  • Vaccination with diphtheria–tetanus–pertussis, hepatitis B and Haemophilus
  • See http://www.who.int/vaccine_safety/topics/hepatitisb/multiple_sclerosis/oct_2008/en/index/html
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