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.