The immunogenicity, safety, and consistency of an Indonesia combined DTP-HB-Hib vaccine in expanded program on immunization schedule

This study analyzed the immunogenicity, safety, and consistency of the new combined
DTP-HB-Hib vaccine produced by Bio Farma, when administered according the early and
accelerated EPI schedule at 6, 10 and 14 weeks of age, with prior administration of
a birth dose of hepatitis B vaccine, as recommended in Indonesia. The present study
was conducted to generate data to support licensure of combined DTP-HB-Hib vaccine
in Indonesia.

Combined vaccines have become an integral part of global childhood immunization programs
and are generally highly acceptable to parents due to the relative ease of administering
multiple antigens at a single visit. Multivalent vaccines have been shown to minimize
the number of injection, increase compliance with the immunization schedule, increase
immunization coverage, decrease exposure to vaccine excipients 16], and reduce logistic costs of vaccine delivery including number of visits to health
centers, number of syringes and needles required, and necessary storage space 17], 18].

An important consideration in national immunization programs, particularly in the
developing countries, is the cost effectiveness of vaccines. Gessner et al. found
that for the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in
1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9 % of mortality
among under-five children. The total incremental societal costs of introducing Hib
vaccine in monovalent and multivalent (DTP-HB-Hib) presentations were, respectively,
US$11.74 and $8.93 for each child. Annual discounted treatment costs averted amounted
to 20 % of multivalent vaccine costs. For the multivalent vaccine, the incremental
costs for every discounted death and disability adjusted life-year averted amounted
to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine 19].

PRP-TT was considered to be efficacious and was approved for use in infants beginning
at 6 weeks of age, without the need to perform an efficacy trial. Conceivably, the
lower immunogenicity of the combination vaccines might not decrease protection among
vaccinated children but could result in less-durable immunity or less-effective control
of Hib colonization or transmission 20]. A further surveillance study will be required to evaluate decline incidence of Hib
disease associated with the investigational DTP-HB-Hib combination vaccine.

The majority of subjects (ranging between 84 and 100 %) in each vaccine group achieved
serum antibody concentration indicative of protection against diphtheria, tetanus,
pertussis, hepatitis B, and Hib after 3-dose primary vaccination series. Other studies
conducted in India and Philippines that used the same accelerated EPI schedule but
vaccinated with different DTP-HB-Hib vaccine showed seroprotection rates similar to
those observed in the present study 7], 8], 18], 21], 22].

Gatchalian et al. vaccinated 94 healthy Philippines infants with DTPw-HBV/Hib
₁₀
(Tritanrixâ„¢-HepB and Hiberixâ„¢, GlaxoSmithKline Biologicals, Rixensart, Belgium) with
a schedule of 6, 10, and 14 weeks of age, without prior hepatitis B vaccination at
birth. One month after the third dose, 100.0 and 94.7 % of subjects had anti-PRP concentration
?0.15 and ?1.0 ?g/ml; 92.6, 100.0 and 78.5 % of subjects had seroprotective concentration
against diphtheria, tetanus, and hepatitis B; and 98.9 % had pertussis vaccine response,
respectively 8]. Chatterjee et al. vaccinated 89 healthy Indian infants, who had received one dose
of the Hep B vaccine within 1 week of birth, with DTPw-HBV/Hib
₁₀
(Tritanrix™-HepB and Hiberix™) with a schedule of 6, 10, and 14 weeks of age. One
month after the third dose, 100.0 % of subjects had anti-PRP concentration ?1.0 ?g/ml
and seroprotective concentration against tetanus and hepatitis B; and 98.9 % of subjects
had anti-diphtheria ?0.1 IU/ml and vaccine response for anti-BPT (Bordetella pertussis) 22].

Of interest is the finding that in this study, transplacentally acquired antibody
concentration for anti-tetanus toxoid were present in all subjects before primary
vaccination series. High transplacentally acquired anti-tetanus toxoid concentration
are common in Indonesia, where programs for the prevention of neonatal tetanus are
implemented by vaccination to pregnant women. In addition, 30.4, 15.8 and 27.7 % of
subjects had seroprotective antibody concentration against diphtheria, hepatitis B
surface, and Hib before primary vaccination series. Our results indicated that the
immune response to the investigational DTP-HB-Hib combination vaccine is not negatively
influenced by the presence of transplacentally acquired antibody concentration. Although
there was evidence of the presence transplacentally acquired antibodies at 6–11 weeks
of age, the GMC values showed a marked increase after 3-dose primary vaccination series,
thereby demonstrating a vaccine response in the subjects.

During the study period, the investigational DTP-HB-Hib combination vaccine elicited
similar proportions of solicited local and systemic reaction between the vaccine groups.
The incidence of local and systemic reactions decreased with successive doses of primary
vaccination. Pain and irritability were the most frequent solicited local and systemic
reactions in each vaccine group. Fewer than 3 % of local or systemic reactions were
reported as severe after any dose in either group. Fever of any severity was reported
at lower rates among all subjects after any dose. Fever with the first dose is of
particular importance, because fever in young infants is often considered as possibly
representing sepsis and thus may lead to medical and laboratory evaluation, including
a visit to the physician’s office or emergency department and diagnostic testing for
possible systemic infection.

In the other studies, local reactions including redness, swelling, and pain at the
site of injection usually started within 1 day after vaccination and last for 1–3
days. Less commonly, children may develop a fever or be irritable for a short period.
When the Hib vaccine was given at the same time as DTP, the rate of fever or irritability,
or both, was no higher than when DTP was given alone 2]. In this study, the percentage of local and systemic reactions following 3-dose primary
vaccination series was within the range reported for DTP-HB-based combination vaccine
and licensed-equivalent vaccine 9], 21], 23]–25]. Addition of each vaccine component to the DTP-HB-Hib combination kept safety profile
of the investigational DTP-HB-Hib combination vaccine appeared to be similar to that
of the DTP-HB-based combination vaccine and licensed-equivalent vaccines.

Lot-to-lot consistency for the investigational DTP-HB-Hib combination vaccine was
demonstrated for all vaccine antigens. The upper limit of the 95 % CI for the difference
between the vaccine groups in seroprotection or vaccine response rates was less than
the predefined limit of 10 % for all antigens. Based on this finding, data for the
three vaccine lots used in this study were pooled for comparison against each lot.
This result provided empirical evidence of consistency between lot productions, which
had also been verified through quality control protocols.

In Bhutan, five cases of encephalopathy and/or meningoencephalitis were reported after
introduction of pentavalent vaccination in 2009. In 2012–2013, India introduced the
similar vaccine resulted in 83 AEFI cases. As many as 43 serious AEFI cases including
27 fatal outcomes were also reported in Vietnam after introduction of pentavalent
vaccine from Crucell in 2010–2013. All of these serious AEFI cases in each country
were reviewed with independent national and international experts 11].

The safety profile of DTP-HB-Hib vaccine could be explored further in next phase.
Some serious AEFIs which had not occurred in phase three study would occurred in phase
four study. Hence, more accurate safety profile could be obtained for implementation
of combination vaccines in the future.