A combined vaccine against diphtheria, tetanus, and pertussis (DTP), which contained whole-cell pertussis (DTwP), was introduced in 1948 [1]. Its acellular pertussis equivalent (DTaP) became available in the early 1990s [1]. DTP vaccines have since been combined with other vaccine antigens (Haemophilus influenzae type b [Hib], poliomyelitis, hepatitis B [HepB] virus [HBV]) to make pentavalent vaccines such as DPT-HBV-Hib and DTaP-IPV/Hib. Vaccines containing antigens against all six diseases have also been manufactured. The hexavalent vaccines offer the general benefits of higher valent combination vaccines for children, parents and healthcare providers [3-5]. This review discusses the evidence related to the use of the hexavalent vaccines that are currently licensed in India (Fig.1). This narrative review was done following a comprehensive search of electronic databases in English and was undertaken with broad overview of topic-related search in Pub Med, and Embase for the period 2000-2018 with keywords "hexavalent vaccines", "DTP", "immunogenicity", "pertussis", and "India" used alone or in combination. Additional relevant information from prescribing information (and related referred studies within it), government websites, and World Health Organization (WHO) website were also considered.

Fig. 1 The study in context.

During the first two years of life, the Universal Immunization Program (UIP) in India recommends vaccination against the six diseases covered by the hexavalent vaccines with: oral poliovirus (OPV) and HBV vaccines at birth; pentavalent DPT-HBV-Hib plus OPV at age 6, 10, and 14 weeks; fractional doses (1/5 full dose, intradermal route) of inactivated polio vaccine (IPV) at 6 and 14 weeks; and boosters of OPV and DTP at 16-24 months [6].

For private practitioners, the Indian Academy of Pediatrics (IAP) recommends OPV and HBV vaccines at birth; DTP, HBV, and Hib (or pentavalent vaccine), and intramuscular IPV at age 6-10-14 weeks; and DTP, Hib, and IPV at 16-18 months [7].

The most notable difference between the UIP [6] and IAP [7] schedules is that they recommend fractional and intramuscular IPV, respectively. This relates to recent WHO recommendations on immunization against poliomyelitis [8]. Rarely, the Sabin poliovirus strains in OPV can cause vaccine-associated paralytic polio; they can also mutate to circulating vaccine-derived polio virus (cVDPV), which can cause outbreaks [9]. It was therefore decided to phase out use of OPV and replace them with IPV [10]. As wild type 2 poliovirus has been eradicated worldwide and 90% of circulating vaccine-derived polio virus cases were caused by Sabin type 2 poliovirus [9], the first step in this transfer was to replace trivalent OPV – which contains types 1, 2, and 3 – with bivalent OPV that contains types 1 and 3. However, to provide protection against type 2, at least one full dose of IPV (which contains all three types) also needs to be administered [10,11].

Due to the resultant worldwide requirement for IPV, there are some problems with supply [12]. One way to overcome this issue is to use two fractional intradermal IPV doses, which contain one-fifth of the dose [10], instead of one full intramuscular dose. The worldwide switch to bivalent OPV took place in April 2016 and fractional IPV was introduced into the UIP [6,10,13]. IAP has already taken the next step and switched completely to three full doses of IPV in the primary series, with a booster dose in the second year of life whenever possible [7]. This IPV schedule is consistent with countries that have withdrawn OPV and instead use IPV as a 2- or 3-dose primary series in infancy, with 0 or 1 booster dose at 6-24 months, and 0 or 1 preschool booster dose [11].

Animal studies using the baboon model suggest that wP-containing vaccines predominantly elicit a Th17/Th1 response which may provide a longer lasting protection than the Th1/Th2 response elicited by aP-containing vaccines; also the predominant Th2 (but lower Th1 and Th17) responses seen with aP-containing vaccines may be less effective in clearing B. pertussis and preventing transmission [18]. However, it is important to note that in the baboon studies, the animals were vaccinated with DTaP vaccines without additional antigens such as IPV. This is relevant for the immune response elicited by the hexavalent vaccines because it is described in the literature that the ssRNA of the inactivated polio vaccine has an adjuvant effect via TLR7 and TLR8 [19,20]. In a recent mouse model, it was also shown that addition of a TLR7 agonist to an alum-adjuvanted aP vaccine converts it from a Th2-inducing vaccine to a more Th1/Th17-inducing vaccine with higher protective capacity, equivalent to or greater than that of a wP vaccine in a murine model [21]. In view of this, presence or absence of IPV in combination vaccines may have an impact on the immune response and the protective efficacy of the vaccine against pertussis.In some countries that switched from wP- to aP-containing vaccines, there was a resurgence in pertussis several years after the switch [18]. This may have been due to shorter duration of protection and lower impact of transmission seen with aP-containing vaccination. However, pertussis resurgence is not universal and the incidence of pertussis already increased in some countries before the switch to aP vaccines [22,23]. Following evaluation of data from 19 middle/high-income countries, WHO concluded that there was "no evidence of a widespread resurgence" of pertussis [18,24]. Increases in pertussis cases were mostly attributed to naturally occurring cyclic patterns [18,24]. Other factors that could have contributed to the increase in cases included higher pertussis awareness, improved surveillance, and better diagnostic techniques [18,25]. It is noteworthy that no country that switched from wP to aP is considering reverting to wP, probably because this could result in poor acceptance, lower uptake, and increased disease burden even if wP vaccines could potentially offer higher efficacy and longer protection [26]. Further, examination of pertussis incidence trends from 20 countries that switched from wP- to aP-containing vaccines did not indicate a correlation between switch date and pertussis incidence [27].

In 2013, the IAP recommended wP-containing vaccines for the primary series [28], but in the 2018 revision, it stated that either DTwP or DTaP can be used, with the primary aim of increasing vaccination coverage [7]. When vaccinating healthy children in private practice, both benefits and risks must be considered when deciding whether to use aP- or wP-containing vaccines. While both are effective in preventing pertussis, both are associated with waning immunity and require booster doses. Regarding safety, aP-containing vaccines have been associated with a more favorable safety profile than wP-containing vaccines [16,29].

Hexavalent vaccines provide the required antigens for the primary series (6-10-14 weeks), but can also be considered for 16-18-month booster vaccination according to the IAP schedule, involving an additional HBV dose [30]. This would likely be acceptable as the US ACIP has recommended that administering extra antigen(s) in a combination vaccine "is often permissible if doing so will reduce the number of injections required" and "an extra dose of Hib or HepB vaccine may be administered as part of a combination vaccine to complete a vaccination series" [2]. Further, five doses of HBV vaccine (birth, three primary, one booster) has been assessed in trials with hexavalent vaccines [31,32], and this number of anti-HBV doses did not appear to affect the vaccine safety profiles. In both trials, there were multi-fold increases in hepatitis B surface antigen (HBs) titers one month after booster vaccination compared to one month after primary vaccinations, regardless of whether a birth dose of HBV vaccine had been administered or not.

Three IPV-containing hexavalent vaccines are available in India: DTwP-Hib/HepB-IPV (Panacea Biotec [33]), DTaP-IPV-HB-PRP~T (Sanofi Pasteur [34]), and DTaP-HBV-IPV/Hib (GSK [35,36]) (Table I).The main difference in their composition is that DTwP-Hib/HepB-IPV contains a wP component [33], DTaP-IPV-HB-PRP~T contains two aP components [34], and DTaP-HBV-IPV/Hib contains three aP components [35,36]. We will therefore refer to them as wP-hexa, 2aP-hexa, and 3aP-hexa, respectively. wP-hexa has been available since 2017 and is only available in India. 2aP-hexa was launched in 2013 and has been available in India since 2016. 3aP-hexa was launched in 2000 and has been available in India since 2018.

TABLE I Overview of Hexavalent Vaccines Currently Available in India 

Published results are available from one phase 3 wP-hexa study, conducted in India [37], in which it was administered as a primary series at 6-10-14 weeks. 2aP-hexa and 3aP-hexa have been studied in a number of different dosing schedules, including 2- or 3-dose primary series (Table I) and as a booster during the second year of life [34-36] in several countries.

One phase 3 study in Indian infants for each of the three hexavalent vaccines has been published [37-39] (Table II). In the wP-hexa study, 284 healthy Indian infants were randomized to wP-hexa or pentavalent DTwP-HBV-Hib plus IPV at 6-10-14 weeks [37]; it is unclear whether all infants had received birth doses of HBV and OPV vaccines. In the 2aP-hexa study, 177 healthy Indian infants who had received birth doses of HBV and OPV vaccines received 2aP-hexa at 6-10-14 weeks [38]. In the 3aP-hexa study, 224 Indian infants who had received birth doses of HBV and OPV vaccines were randomized 1:1 to 3aP-hexa at 6-10-14 weeks or 2-4-6 months [39].

TABLE II	Seroprotection/Vaccine Response Rates One month after Primary Vaccination with Three Doses of Hexavalent Vaccine 
(at 6-10-14 weeks) in Indian Infants Who Had Received a Birth Dose of HBV Vaccinea 

TABLE II	Seroprotection/Vaccine Response Rates One month after Primary Vaccination with Three Doses of 
Hexavalent Vaccine (at 6-10-14 weeks) in Indian Infants Who Had Received a Birth Dose of HBV Vaccinea 

Vaccine response (pertussis antigens) and seroprotection (other antigens) results 1 month after primary vaccination with a hexavalent vaccine at 6-10-14 weeks are shown in Table II. It should be noted that the definitions of vaccine response and seroprotection varied between the studies [37-40]. As there is no established correlate of protection for pertussis, anti-PT or pertussis immunoglobulin G levels were used to assess vaccine response against pertussis components and considered as surrogate markers for protection. Pertussis vaccine response results for wP-hexa were comparable to wP-penta for anti-PT (68.4% vs. 66.2%) and pertussis immunoglobulin G (75.7% vs. 72.8%); seroprotection rates for the other antigens were 88.2-100% [37] (Table II). For 2aP-hexa, pertussis vaccine response results were 93.8% (anti-PT) and 99.3% (anti-FHA) [38]. Seroprotection rates were >99% for most antigens. Diphtheria seroprotection rates were 99.3% and 49.6%, respectively based on anti-diphtheria antibodies cut-off of 0.01 IU/mL and the WHO-recommended full protective cut-off (0.1 IU/mL) [38,41]. For 3aP-hexa, vaccine response rates for the three pertussis antigens were 97.0-100% and seroprotection rates for the other five antigens were 98.6-100% [39].

TABLE III Adverse Events After Vaccination with Hexavalent Vaccine at 6-10-14  weeks in Indian Infantsa

In the study that compared wP-hexa with pentavalent DTwP-HBV-Hib plus IPV, immunogenicity results were comparable with both regimens [37]. Similarly, in the study that compared two different dosing schedules (6-10-14 weeks and 2-4-6 months) of 3aP-hexa, immunogenicity results were similar with both schedules [39].

Safety results for the three Indian studies are summarized in Table III [37-40]. The most common solicited local adverse events (AEs) were pain/tenderness (wP-hexa and 2aP-hexa) and pain (3aP-hexa); while the most common solicited systemic AEs were fever (wP-hexa), irritability (2aP-hexa), and temperature (3aP-hexa) [37-40]. Serious adverse events were rare (<2% in each study) and none were judged to be related to vaccination [37-39]. All three studies reported that the hexavalent vaccines were well tolerated [37-39].

In the study that compared wP-hexa with pentavalent DTwP-HBV-Hib plus IPV, reactogenicity and safety results were comparable with both regimens [37]. In the study that compared two different dosing schedules of 3aP-hexa, safety results were similar, although pain was more often reported in the 6-10-14-week group vs. the 2-4-6-month group (25.2% vs 13.4%) [39].

If hexavalent combination vaccines are used in the Indian schedule, they would likely be co-administered with rotavirus and/or pneumococcal conjugate vaccines (PCVs) at 6-10-14 weeks [6,7], and could also be
co-administered with measles-mumps-rubella
(MMR), varicella, measles-mumps-rubella-varicella (MMRV), and/or hepatitis A vaccines in the second year of life [7].

There are no published studies of wP-hexa co-administered with other routine vaccines, but the product leaflet states that it can be given at the same time as PCVs and MMR and rotavirus vaccines [33].

2aP-hexa has been evaluated in co-administration studies outside India, and data suggest no clinically relevant interference on concomitant administration with PCV, MMR, rotavirus, or meningococcal conjugate vaccines [46]. In a South African study in which 15-18-month-old toddlers received a booster dose of 2aP-hexa concomitant with MMR and varicella vaccines, the response to the varicella vaccine was slightly lower than would be expected [32]. Due to a potentially clinically relevant interference in the antibody response of varicella vaccine, 2aP-hexa and varicella vaccines should not be administered at the same time [46].

3aP-hexa is the only hexavalent vaccine available in India that has prospective clinical data in preterm infants (and includes such information in its label) which indicates that 3aP-hexa has a similar immunogenicity and safety profile in preterm and full-term infants. Cardiorespiratory events in preterm infants of <28 weeks gestation were observed, but this seemed to be influenced by the infantss underlying condition as the cardiorespiratory risk in this population is a point of attention for the prescriber/vaccinator in general and most resolved spontaneously or with minimal intervention [63].

Use of combination vaccines is a practical way to reduce the number of injections given to infants and children. Vaccination schedules can also be simplified with the use of hexavalent combination vaccines for primary and booster vaccination. Three IPV-containing hexavalent vaccines are available in India. The level of available evidence and experience with these three vaccines vary widely [64-66]. All three vaccines evoke immune responses to their contained antigens in phase 3 studies in Indian children using the 6-10-14-week schedule for the primary series [37-39]. 2aP-hexa and 3aP-hexa have also been shown to be immunogenic when tested as a booster dose in the second year of life following a 6-10-14-week primary series [31,32]. All three hexavalent vaccines are well tolerated; although whole-cell pertussis containing vaccines may result in more solicited local reactions and fever than those with acellular pertussis components.

Acknowledgements: The authors would like to thank the Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Thibaud André (Business & Decision Life Sciences) coordinated the manuscript development and provided editorial support. Jenny Lloyd (Compass Medical Communications Ltd.) provided writing support.

Contributors: All authors provided substantial intellectual and scientific input during manuscript development, critically reviewed the content, revised the manuscript, and approved the final version.

Funding: GlaxoSmithKline Biologicals SA took charge of all costs associated with the development and publication of this manuscript.

Competing interests: AC: has received lecture fees and advisory board fees from Sanofi Pasteur and Abbott Vaccines; RP,AM,SK: are employees of the GSK group of companies; AM: has received shares from the GSK group of companies.

Trademarks: Hexaxim is a trademark of Sanofi Pasteur; Imovax Polio is a trademark of Sanofi Pasteur India Pvt. Ltd.; Pentavac SD is a trademark of Serum Institute of India Ltd.; EasySix is a trademark of Panacea Biotec Ltd.; Infanrix hexa and Infanrix are trademarks of the GSK group of companies.

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