Post-authorization safety surveillance of a liquid pentavalent vaccine in Guatemalan children
Introduction
Since 1990, the global coverage for diphtheria, tetanus toxoid and pertussis vaccines (DTP) has steadily increased up to 85% [1], [2]. In 1992, WHO recommended the addition of hepatitis B vaccine (HBV), and in 2005, Haemophilus influenzae type b conjugated vaccines into the expanded program of immunization. With the increasing number of vaccine antigens administered in early infancy, combination vaccines for children's immunization programs have helped reduce the number of injections, reduce the number of clinic visits, and increase parental compliance [3]. For low and middle-income countries, fully liquid combination vaccines that are ready to use simplify and improve the efficiency of immunization delivery and avoid programmatic errors associated with reconstitution of separate products [4].
Vaccine safety monitoring prior to registration or licensure is reviewed by national, regional and global regulatory authorities. However, at the time of registration, limited safety data are available. To detect rare or unexpected adverse events following immunization (AEFI) surveillance studies are required after deployment in the population. In low and middle-income countries, the lower accessibility to the health care system and limited capacity for pharmacovigilance surveillance can limit collection of safety data; therefore perceptions of vaccine safety arising when serious AEFIs are reported, even when events are coincidental and expected, may derail immunization programs [4], [5]. New post-licensure study methods have been developed in upper income countries that provide data to help identify rare SAEs and reassure the population and immunization programs about the safety of newly introduced vaccines [6].
The immunogenicity and safety of a fully liquid pentavalent vaccine Quinvaxem® was demonstrated in clinical trials of healthy infants [7], [8], [9]. Nevertheless, in Sri Lanka, after introduction of this liquid pentavalent vaccine by the national program, individual case reports of deaths and hypotonic-hyporesponsive episodes (HHEs) were reported and vaccination was interrupted. The incidence of HHE of 14.9 cases per 100,000 doses was found to be well within the reported estimated rate of HHE incidence following vaccination with whole-cell pertussis-containing vaccines (21–250 cases per 100,000 doses). The program in Sri Lanka was later reinitiated as the clinical and epidemiological data showed no evidence of an unexpected safety profile of Quinvaxem® and no significant increase in the incidence of recognized adverse events when compared with the previous whole-cell pertussis vaccine in use [10].
This observational study was designed as part of the WHO prequalification post-registration process to provide further information on important safety outcomes for infants receiving a primary immunization series with Quinvaxem® as it was delivered as part of the public immunization system in Guatemala. We set up a monitoring system to examine patterns of clinic and emergency department (ED) visits, hospitalizations and deaths following vaccination using a self-controlled case series design that has been shown to be useful in higher income countries [11], [12], [13].
Section snippets
Methods
This was an open label, active surveillance prospective cohort study that evaluated the safety of a fully liquid DTwP-HepB-Hib vaccine administered to healthy infants at 2, 4 and 6 months of age under the routine national immunization schedule in Guatemala. This report also includes a post hoc exploratory self-controlled case series analysis. The Center for Health Studies at University del Valle and the Johns Hopkins Bloomberg School of Public Health managed the data collection and analysis.
Results
Among the 3000 eligible infants enrolled from December 2008 through January 2010; 1543 (51.4%) were female (Table 1). The mean age at enrolment and first vaccination was 2.4 (SD = 0.8) months. All infants received at least one dose of vaccine, and 2812 (93.7%) completed the three dose primary schedule (Fig. 1). The mean ages at second and third vaccination were 4.2 (SD = 1.0) and 6.5 (SD = 1.2) months. There were 143 (4.8%) premature births, and 208 (6.9%) infants, although healthy at enrolment,
Discussion
Quinvaxem®, a fully liquid combination (pentavalent) DTwP-HepB-Hib vaccine in use by many national immunization programs in lower and middle-income countries around the world, was associated with lower than expected rates of SAEs when administered to Guatemalan infants in the routine program. No increase in the rate of health care utilization was seen in the immediate post-vaccination period compared to control time periods. This active vaccine safety surveillance program established at IGSS
Conclusions
Pentavalent DTwP-HepB-Hib vaccines are important for the prevention and control of severe infectious diseases prevalent in low and middle-income countries. The post-licensure experience in Guatemala following the use of Quinvaxem® vaccine has confirmed the safety documented in clinical trials with no unexpected medically attended adverse events in the post-vaccination period.
Conflicts of interest
At the time of the study, K. Hartman was contractor of Crucell Switzerland AG. M. Rauscher is an employee of Crucell Switzerland AG. NA Halsey has served on safety monitoring committees for Merck and Novartis, and EJ Asturias on safety monitoring board for sanofi Pasteur.
Authors contributions
EJ Asturias, NA Halsey, and K Hartman designed the protocol, lead the conduction of the study and the analysis of the data. IL Contreras-Roldan coordinated the study sites and reviewed and classified the adverse events. M Ram and L Moulton performed the independent statistical analysis. K Hartman led the pharmacovigilance review and classifications. M Rauscher contributed to the pre-specified analysis and reporting of the study and critically reviewed the manuscript.
Acknowledgements
We recognize the contributions made by the physicians and nurses at IGSS who cared and provided immunizations for the subjects during the study. We will also like to thank L. Santos who directed the research nurses, JG Rivera for data management, and B Lerdo-Tejada for the monitoring of the study.
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