Home            Past Issues            About IP            About IAP           Author Information            Subscription            Advertisement              Search  

   
guidelines

Indian Pediatr 2014;51: 785-803

Indian Academy of Pediatrics (IAP) Recommended Immunization Schedule for Children Aged 0 through 18 years – India, 2014 and Updates on Immunization


Vipin M Vashishtha, Panna Choudhury, Ajay Kalra, Anuradha Bose, Naveen Thacker,
Vijay N Yewale, CP Bansal and Pravin J Mehta

Indian Academy of Pediatrics, Advisory Committee on Vaccines and Immunization Practices (ACVIP)

Correspondence to: Dr Vipin M Vashishtha, Convener, IAP Advisory Committee on Vaccines and Immunization Practices, Mangla Hospital and Research Center, Shakti Chowk, Bijnor, Uttar Pradesh 246 701, India.
Email: vipinipsita@gmail.com
 

 


Justification:
There is a need to review/revise recommendations about existing vaccines in light of recent developments in the field of vaccinology.

Process: Following an IAP ACVIP meeting on April 19 and 20, 2014, a draft of revised recommendations for the year 2014 and updates on certain vaccine formulations was prepared and circulated among the meeting participants to arrive at a consensus.

Objectives: To review and revise recommendations for 2014 Immunization timetable for pediatricians in office practice and issue statements on certain new and existing vaccine formulations.

Recommendations: The major changes in the 2014 Immunization Timetable include two doses of MMR vaccine at 9 and 15 months of age, single dose recommendation for administration of live attenuated H2 strain hepatitis A vaccine, inclusion of two new situations in ‘high-risk category of children’ in context with ‘pre-exposure prophylaxis’ of rabies, creation of a new slot at 9-12 months of age for typhoid conjugate vaccine for primary immunization, and recommendation of two doses of human papilloma virus vaccines with a minimum interval of 6 months between doses for primary schedule of adolescent/preadolescent girls aged 9-14 years. There would not be any change to the committee’s last year’s (2013) recommendations on pertussis vaccination and administration schedule of monovalent human rotavirus vaccine. There is no need of providing additional doses of whole-cell pertussis vaccine to children who have earlier completed their primary schedule with acellular pertussis vaccine-containing products. A brief update on the new Indian Rotavirus vaccine, 116E is also provided. The committee has reviewed and offered its recommendations on the currently available pentavalent vaccine (DTwP+Hib+Hepatitis-B) combinations in Indian market. The comments and footnotes for several vaccines are also updated and revised.

Keywords: Immunity, Child, Guidelines, MMR Vaccine, Vaccination.


The IAP Advisory Committee on Vaccines and Immunization Practices (ACVIP) has recently reviewed and revised the recommended immunization schedule for children aged 0 through 18 years to ensure that the schedule reflects recommendations based on recent evidences for licensed vaccines in the country. The first annual meeting of the IAP ACVIP was held on 19th and 20th April 2014 in New Delhi. IAP ACVIP members and invited experts who attended the meeting are listed in Annexure 1. The aim of the meeting was to discuss and debate recent developments in the field, to revise recommendations for the IAP Immunization Timetable for the year 2014, and to issue recommendations for available licensed vaccines in the country. Following the meeting, a draft of revised immunization schedule for the year 2014 was prepared and circulated among the meeting participants to arrive at a consensus.

The detailed process behind issuing IAP recommen-dations on immunization – primarily for the pediatricians in office practice has been described earlier [1]. These recommendations provide guidelines to a pediatrician on how best to utilize available licensed vaccines in their office-practice settings. The members may use their own discretion while using them in a given situation within the framework suggested [2]. The existing National immunization schedule and government policies are also taken into account while drafting recommendations.

Aims and Objectives

To revise IAP Immunization Timetable for the year 2014, and review and issue recommendations on the available licensed vaccines.

Recommendations for IAP Immunization Timetable, 2014

The IAP ACVIP has issued recommendations for the IAP Immunization Timetable (Table I and Fig. 1) for the year 2014 that includes the following major changes from last year:

TABLE I IAP Immunization Timetable 2014

I. IAP recommended vaccines for routine use
Age (completed wks/mo/y) Vaccines
Comments
Birth BCG Administer these vaccines to all newborns before hospital discharge
OPV 0
Hep-B 1
6 weeks DTwP 1 DTP:
IPV 1 • DTaP vaccine/combinations should preferably be avoided for the primary series
Hep-B 2
Hib 1
• DTaP vaccine/combinations should be preferred in  certain specific circumstances/conditions only
Rotavirus 1
PCV 1 • No need of repeating/giving additional doses of whole-cell pertussis (wP) vaccine to a child who has earlier completed their primary schedule with acellular pertussis (aP) vaccine-containing products
Polio:
• All doses of IPV may be replaced with OPV if administration of the former is not feasible
• Additional doses of OPV on all supplementary immunization activities (SIAs)
• Two doses of IPV instead of 3 for primary series if started at 8 weeks, and 8 weeks interval between the doses
• No child should leave the facility without polio immunization (IPV or OPV), if indicated by the schedule
Rotavirus: 
• 2 doses of RV1 and 3 doses of RV5
• RV1 should be employed in 10 and 14 week schedule, instead of  6 and 10 week
• 10 and 14 week schedule of RV1 is found to be far more immunogenic than existing 6 and 10 week schedule
10 weeks DTwP 2 Rotavirus:
IPV 2 • If RV1 is chosen, the first dose should be given at 10 weeks
Hib 2
Rotavirus 2
PCV 2  
14 weeks DTwP 3 Rotavirus:
IPV 3 • Only 2 doses of RV1 are recommended at present
Hib 3 • If RV1 is chosen, the 2nd dose should be given at 14 weeks
Rotavirus 3
PCV 3
6 months OPV 1 Hepatitis-B:
Hep-B 3 • The final (third or fourth) dose in the HepB vaccine series should be administered no earlier than age 24 weeks and at least 16 weeks after the first dose
9 months OPV 2 MMR:
MMR-1 • Measles-containing vaccine ideally should not be administered before completing 270 days or 9 months of life
• The 2nd dose must follow in 2nd year of life
• No need to give stand-alone measles vaccine
Typhoid:
9-12 months

Typhoid Conjugate Vaccine • Currently, two typhoid conjugate vaccines, Typbar-TCV and PedaTyph available in Indian market
• PedaTyph is not yet approved; the recommendation is  applicable to Typbar-TCV only
• An interval of at least 4 weeks with the MMR vaccine should be maintained while administering this vaccine
• Should follow a booster at 2 years of age
12 months Hep-A 1 Hepatitis A:
• Single dose for live attenuated H2-strain Hep-A vaccine
• Two doses for all killed Hep-A vaccines are recommended now
15 months MMR 2 MMR:
Varicella 1 • The 2nd dose must follow in 2nd year of life
PCV booster • However, it can be given at anytime 4-8 weeks after the 1st dose during 2nd year
16 to 18 months
DTwP B1/DTaP B1 Varicella:
IPV B1, Hib B1 • The risk of breakthrough varicella is lower if given 15 months onwards
    • The first booster (4th dose) may be administered as early as age 12 months, provided at least 6 months have elapsed since the third dose.
DTP:
• First and second boosters should preferably be of DTwP
• Considering a higher reactogenicity of DTwP, DTaP can be considered for the boosters
18 months Hep-A 2 • 2nd dose for killed vaccines; only single dose for live attenuated H2- strain vaccine
2 years Typhoid booster • Either Typbar-TCV® or Vi-polysaccharide (Vi-PS) can be employed as booster;
• Typhoid revaccination every 3 years, if Vi-polysaccharide vaccine is used
• Need of revaccination following a booster of Typbar-TCV® not yet determined
4  to 6 years
DTwP B2/DTaP B2 Varicella:
OPV 3 Varicella 2 • 2nd dose can be given at anytime 3 months after the 1st dose
Typhoid booster  
10 to 12 years Tdap/Td Tdap:
HPV • Tdap is preferred to Td followed by Td every 10 years
HPV:
• Only 2 doses of either of the two HPV vaccines for adolescent/pre-adolescent girls aged 9-14 years
• For girls 15 years and older, and immunocompromised individuals 3 doses are recommended
• For two-dose schedule, the minimum interval between doses should be 6 months.
• For 3 dose schedule, the doses can be administered at 0, 1-2 (depending on brands) and 6 months
II. IAP recommended vaccines for High-risk* children (Vaccines under special circumstances)

1-Influenza Vaccine

2-Meningococcal Vaccine

3-Japanese Encephalitis Vaccine

4-Cholera Vaccine

5-Rabies Vaccine

6-Yellow Fever Vaccine

7-Pneumococcal Polysaccharide vaccine (PPSV 23)

* High-risk category of children:  Congenital or acquired immunodeficiency (including HIV infection); Chronic cardiac, pulmonary (including asthma if treated with prolonged high-dose oral corticosteroids), hematologic, renal (including nephrotic syndrome) and liver disease; Children on long term steroids, salicylates, immunosuppressive or radiation therapy; Diabetes mellitus, Cerebrospinal fluid leak, Cochlear implant, Malignancies; Children with functional/ anatomic asplenia/ hyposplenia; During disease outbreaks; Laboratory personnel and healthcare workers; Travelers; Children having pets in home; Children perceived with higher threat of being bitten by dogs such as hostellers, risk of stray dog menace while going outdoor.

A. Measles and MMR vaccination

Recommendation: The committee has revised its recommendations on Measles and MMR vaccination schedule. The new schedule will have a dose of MMR at 9 months instead of measles, and another dose (2nd) at 15 months of age. The earlier recommendation of 2nd dose of MMR at 4-6 years of age has been removed.

The need and justification: NTAGI Standing Technical Sub-Committee (STSC) recommended two doses of Measles – Rubella (MR) vaccines in the Universal immunization program (UIP) at 9 months and 16-24 months at the time of 1st booster of DTP vaccine. Since the Academy has argued very strongly in favor of MMR instead of MR vaccine in UIP schedule, the revised recommendations will facilitate inclusion of Mumps vaccine in the National immunization program in near future. Furthermore, it will be more in sync with the upcoming UIP schedule. The detailed reasons are discussed in another recent position paper from IAP publication [3].

The evidence: There are many studies both from India and from other countries demonstrating efficacy and safety of MMR vaccine given at 9 month of age [3-8].

B. Live attenuated Hepatitis A vaccine

Recommendation: The committee has revised its recommendations on administration schedule of live attenuated hepatitis A vaccine, based on the viral H2 strain (Chinese vaccine). Now a single dose of this vaccine is recommended at 12 months of age over-riding the previous recommendation [9] of two doses of the same vaccine.

The justification and evidence: The committee reviewed both published [11,12] and unpublished long term follow-up data on immunogenicity and safety of a single dose of this vaccine from trials in India. The data showed 79.3% of 121 children were seroprotected (anti-HAV titers >20 mIU/mL) up to 6 years follow-up in the pivotal single center study, whereas 97.3% of 111 children had shown seroprotection after 5 years of follow-up period in the multi-centric group. In the multi-centric study [12], the test subjects maintained good GMT levels even after 5 years of follow-up. The committee had earlier shown its concern on waning of seroprotection in a subgroup of individuals of original single-center study cohort [2]. However, it was later disclosed that only ten subjects had shown this phenomenon, and most of these subjects were of comparatively higher age groups than other study subjects. The decision was also facilitated by the SAGE/WHO recommendations of single dose of live attenuated hepatitis A vaccine [10].

C. Rotavirus Vaccines

Monovalent rotavirus vaccine, RV1

The committee reviewed new data on administration schedule of RV1 (Rotarix) from Pakistan [13] and Ghana [14]. In both studies, the seroconversion and GMTs were higher at delayed (10 and 14 weeks) than early (6 and 10 weeks) schedule, though not statistically significant [13, 14]. In Ghana study, the seroconversion and GMTs were significantly higher in 3-dose (6, 10 and 14 week) schedule than 2-dose early (6 and 10 week) schedule [14]. As these studies are yet unpublished, full methodology and results are not available for scrutiny. The available results do not warrant any change in the existing schedule of RV1 vaccine that includes the first dose at 10 weeks of age instead of 6 weeks in order to achieve better immune response, and the second dose at 14 weeks to fit with existing National immunization schedule [9].

Indian rotavirus vaccine, 116 E

This vaccine developed by Bharat Biotech (Rotavac) is a live, naturally attenuated vaccine containing monovalent, bovine human reassortant strain characterized as G9 P [11], with the VP4 of bovine rotavirus origin, and all other segments of human rotavirus origin. The vaccine strain was isolated from asymptomatic infants with mild diarrhea by Indian researchers in 1985 at AIIMS, New Delhi. Follow up of these infants indicated that they were protected against severe rotavirus diarrhea for up to 2 years. This strain was sent for vaccine development to the National Institute of Health by Department of Biotechnology, India, and later transferred to Bharat Biotech International Limited in 2001 for further development.

In a phase II study, both low (104 ffu) and high (105 ffu) dosages of 116E were found safe in infants between 8 and 20 weeks of age. IgA immunogenicity rates for the 105 ffu dosage were 64.7% after 1 dose, and 89.7% after 3 doses. The vaccine virus was shed in about 20% of infants [15].

A randomized, double-blind, placebo-controlled phase III clinical trial [16] amongst 6,799 infants was conducted at three sites in India. The first year efficacy against severe rotavirus diarrhea was 53·6% (95% CI 35·0-66·9; P=0·001) with protection continuing into the second year of life also. The vaccine also showed 20% efficacy against all-cause severe diarrhea admission. Six cases of intussusceptions (all occurring after administration of 3rd dose) were recorded in the vaccinees and two in the control group. This vaccine has already been licensed in India and would soon be available for use in Indian market.

The committee reviewed the evidence and opined it to be a moderately effective vaccine against rotavirus diarrhea in India. As this is the only vaccine that has undergone large scale field- efficacy trial in India, the level of evidence regarding its efficacy is rated higher by the committee. However, the committee stresses the need of having large scale studies, particularly post-marketing surveillance to monitor occurrence of acute intussusception amongst vaccinated children. There seems to be one excess case of intussusception for every 2000 children vaccinated. Apparently, the sample size was not adequately powered to look for statistical significance [16]. Regarding use of the vaccine in office-practice, it is not clear whether pediatricians would be able to use it in coming months since information about formulation and commercial availability of the vaccine is not yet available.

D. Pre-exposure prophylaxis for rabies

Recommendations for office practice: The committee has now recommended that practically all children need vaccination against rabies and following two situations to be included in high-risk category of children for rabies vaccination: (i) children having pets at home; and (ii) children perceived with higher threat of being bitten by dogs such as hostellers, and those with risk of stray dog bite while going outdoor. These children should be offered pre-exposure prophylaxis (Pre-EP) against rabies. This must be preceded by a one-to-one discussion with the parents. The Pre-EP is not included in the IAP immunization schedule for all children. Three doses are recommended to be given intramuscularly on days 0, 7 and 28 (day 21 may be used if time is limited, as with imminent travel, but day 28 is preferred). The intradermal schedule has been shown to be effective, but is not approved for this purpose in office practice.

There are studies to show that good antibody levels persist up to 10 years even after a 3 dose pre-exposure prophylaxis followed by a booster at one year. However, on account of the nature of the disease, for re-exposure at any point of time after completed and documented, pre-or post-exposure prophylaxis, two doses are to be given on days 0 and 3. Rabies immunoglobulins (RIG) are not needed in these children. There is no change in the IAP recommendations for post-exposure prophylaxis (PEP) of rabies.

Public use: The committee urges the Government of India (GoI) to urgently take remedial measures to address the huge burden of rabies in India [17]. These measures include public education campaigns, need to ensure the uninterrupted availability of vaccines and anti-rabies immunoglobulin in primary health care facilities and training of primary care providers (including pediatricians), vaccination of dogs, sterilization of stray dogs, and declaration of rabies as a notifiable disease. The committee reiterated its position that universal Pre-EP vaccination, especially for children, could reduce the number of human rabies dramatically. Use of intradermal vaccination would bring down the vaccine cost for universal vaccination program dramatically [2].

Justifications: The advantages of the Pre-EP include elimination of the need for RIG, reduction in the number of vaccine doses on exposure and provision of immunity to individuals whose post-exposure prophylaxis is delayed. Further, the likelihood of lack of documentation of a dog bite amongst young children who may not report scratches and small playful bites from dogs and cats are other reasons why Pre-EP would be useful. However, it was agreed upon that inclusion of Pre-EP in only IAP schedule for office practice would not serve the desired purpose since majority of deaths occur among children belonging to low socioeconomic strata and those living in remote areas [17]. WHO encourages the implementation of carefully designed studies on the feasibility, cost-effectiveness and long-term impact of incorporating ‘Cell Culture Vaccines and Embryonated egg-based vaccines’ (CCEEVs) into the immunization programs of infants and children where canine rabies is a public health problem [18].

E. Typhoid conjugate vaccines

Recommendation for office practice

Primary schedule: The committee has now created a new slot for typhoid conjugate vaccine for primary immunization at 9-12 months of age in the IAP Immunization schedule. There are currently two typhoid conjugate vaccines (Typbar-TCV and PedaTyph), available and licensed in the country. However, this recommendation would be applicable only to the former as the committee is awaiting more data on the latter. Only a single dose of the vaccine is recommended for primary series. An interval of at least 4 weeks with the measles/MMR vaccine should be maintained since the data on interference with the measles/MMR vaccine are not yet available.

Boosters: Those who received a dose of conjugate vaccine at 9-12 months can be prescribed booster of either Vi-polysaccharide (Vi-PS) or the conjugate vaccine at 2 years of age. Those who have received booster of Vi-PS vaccine will need revaccination every 3 years till the intended duration of protection. There is no evidence of hypo-responsiveness on repeated vaccination so far. The need of further boosters after conjugate vaccine is not yet determined since long term data are not yet available.

Catch-up schedule: Catch-up vaccination is recommended throughout the adolescent period, i.e. up to 18 years of age. Below 2 years, only conjugate vaccine is recommended while above 2 years of age any of the two can be employed. The details about further schedule should be followed as described above in the ‘boosters’ section.

Recommendations for public use

The committee strongly urges the GoI to include universal typhoid vaccination in its UIP all over the country at the earliest.

Evidence and justification: The committee believes that considering the epidemiology of typhoid in the country, there is definite need of protection against typhoid fever below 2 years of age. The Vi-PS vaccines are ineffective below 2 years of age and provide modest and short lasting protection. There is definite need of typhoid conjugate vaccines, effective below 2 years of age and capable of providing superior long-lasting protection. The committee reviewed the published [19] and unpublished data of new typhoid conjugate vaccines, (BBIL’s Typbar-TCV, BioMed’s PedaTyph and Novartis’s Vi-CRM197). All these vaccines can be administered at and around 9 months of age. Only a single dose is sufficient for adequate seroconversion for primary immunization, and the second dose failed to show incremental effect on antibody titers (data after 2nd dose of PedaTyph are not yet available). In the published trial of Novartis’s Vi-CRM197 conjugate typhoid vaccine [19], a low response was noted to measles, hepatitis B and H influenza type b both in reference (PCV13) and test vaccine (conjugate typhoid vaccine) groups, with a non-significant reduction in the rate of measles seroconversion in the test vaccine group in one center. The committee has thus recommended maintaining an interval of at least 4 weeks with the measles/MMR vaccine while administering this vaccine. The committee has also asked the manufacturer to undertake a ‘measles/MMR interference study’ with vaccination at 9 months.

Regarding the need and timing of boosters, the data provided by the manufacturer of Typbar-TCV vaccine show almost 100% seroprotection (>7.2 EU/mL) of test vaccine in both the cohorts (6 mo-2 years and 2-45 years) till 18 months of follow-up, although both seroconversion (>4-fold rise of antibody level) and GMT levels waned significantly in both cohorts. Regarding comparison of Vi-PS non-conjugate vaccine with the Vi-PS conjugate vaccine, both fared equally well above 2 years of age as far as immediate and long-term seroconversion are concerned, although the latter had significantly higher GMTs and slightly better seroconversion rates than the former. The committee has thus recommended either of the vaccines as a booster at 2 years of age. The need of repeat doses/boosters for conjugate vaccine shall only be determined after long-term efficacy data are available.

F. Human Papillomavirus (HPV) vaccination schedule

Recommendations: Two doses of HPV vaccine are advised for adolescent/pre-adolescent girls aged 9-14 years; for girls 15 years and older, current 3 dose schedule will continue. For two-dose schedule, the minimum interval between doses should be 6 months. The interval between the first and second dose may be extended upto12 months, should this facilitate administration – say in school settings. For girls, primed before the age of 15 years, even if older at the time of second dose, a two-dose schedule will be applicable. However, for immuno-compromised individuals, including HIV-infected, the three-dose schedule is recommended, irrespective of age.

Evidence and justification: IAP had recommended use of HPV vaccine in its immunization schedule way back in 2007. Though there is no coverage data on uptake of this vaccine through private sector, the common perception is that acceptance is poor and the coverage still remains miniscule. The move to revise HPV vaccine immunization schedule for adolescent girls from existing three to two doses would not only be cost-saving, but would also simplify logistics like increased flexibility of the intervals, and annual doses for school-based delivery. Hence, the revised recommendations may help in improving acceptance, facilitating delivery, and enhancing coverage of the vaccine.

The WHO’s Strategic Advisory Group of Experts (SAGE) working group (WG) on HPV has recommended revision of vaccination schedule for pre-adolescent and adolescent girls from three primary doses to two in its April 2014 meeting [20]. The committee has reviewed the background material and various trials conducted in this regard so far [21]. The main source of evidence is provided by a systematic review commissioned by SAGE WG [22]. The other sources include review of the data from observational studies on 2 versus 3 dose schedule, and proceedings of an Ad hoc Expert Consultation on HPV vaccine schedules organized in Geneva, 2013 [21]. The European Medicines Agency (EMA) has also approved two doses for pre-adolescent and adolescent girls aged 9-14 years for the bivalent HPV vaccine and also offered positive opinion for a similar schedule for quadrivalent vaccine [23]. Many countries have either already adopted or are planning to adopt a two-dose schedule [21]. Few countries like Brazil, Mexico, Columbia and British Columbia are running an extended schedule (2+1, i.e. 0, 6, 60 months) where the last dose at 5 years depends on follow-up assessment of the need [21]. In Costa Rica, strong 4 year protection was reported in women who received just one dose of bivalent HPV vaccine [21].

The systematic review [22] has identified various studies that include both randomized and non-randomized trials of both the vaccines, bivalent and quadrivalent, from various high income group countries like Canada, Australia, Sweden, Denmark, Germany, and low and middle income (LMI) countries like Uganda, Mexico, and India. In randomized comparisons of two-dose and three-dose schedules (overall 3 RCTs), seroconversion and seropositivity were non-inferior or inconclusive at all-time points. In non-randomized comparisons, all available data for seroconversion and seropositivity showed non-inferiority of the 2-dose compared with the 3-dose schedule. The efficacy against virological endpoints in initially HPV-naïve subjects who received 2 doses of bivalent vaccine at 48th month indicates that the two-dose schedule prevents HPV-16/18 infection in subjects who did not receive a complete 3-dose vaccination course. The review also compared different intervals between doses of HPV vaccine. The 6-month interval resulted in superior GMCs compared with the 2-month interval one month after the last vaccine dose in all the age groups enrolled.

The mathematical models also support the two-dose schedule for girls aged 9-14 years. In one such model it was shown that in high-income settings (such as the UK and Canada), if it was documented that a 2-dose vaccination conferred more than 10-20 years protection then adding the third dose would not be cost-effective [21]. The cost-effectiveness of 2-dose vs. 3-dose vaccination in low/middle income settings still needs to be explored.

The committee’s recommendations are also facilitated by the evidence generated by an ongoing multi-centric RCT on alternative dosing schedule of quadrivalent HPV vaccine in India [24-26]. In this trial, comparisons favored the 2-dose schedule and the ratio of antibody levels was higher in the 2-dose group than in 3-dose group [25,26]. The GMCs for HPV18 in the 2-dose group were non-inferior to that in the 3-dose group. However, on clinical outcomes basis, the RCT provided only limited data, and incident infections with any of the vaccine types in the quadrivalent vaccine were more common in the 2-dose than in the 3-dose group [25,26].

The magnitude of the vaccine response is determined by the age at the first dose. The review of different trials have shown that 100% adolescents can be primed with a single dose of the vaccine and the second dose after 6 months results in higher (almost twice) peak titers in adolescents than in adults. These antibodies then plateau for about 12 months after the peak and decline very slowly providing a long lasting protection [21]. There are limited data from HIV-infected individuals receiving a 3-dose schedule and no data from HIV-infected individuals receiving a 2-dose schedule.

The committee concludes that two doses of HPV vaccine in girls 9-14 years of age are non-inferior in terms of immunogenicity when compared to three doses in girls 9-14 years or 15-24 years of age. A 2-dose vaccine schedule is likely to be as efficacious as three doses, even though long-term outcome and clinical efficacy data are not yet available. The committee stresses the need of long-term studies on efficacy/effectiveness of alternative schedules.

G. Update on Pertussis immunization

Recommendation: In lieu with its earlier recommendations on pertussis vaccination [9], the committee clarifies that there is no need of repeating or giving additional doses of whole-cell pertussis (wP) vaccine in order to boost immunity in children who have earlier completed their primary schedule with acellular pertussis (aP) vaccine-containing products. However, it should be ensured that all the remaining doses are wP vaccine-containing products. This is to be reiterated here that wP vaccine is permitted till 7 years of age.

Justification: Although it is reported that presence of even a single dose of wP vaccine in the primary infant series of pertussis immunization was found to be providing superior priming and more durable immunity than the schedule completed with only aP containing vaccines [9,27], nevertheless, the aP vaccines are also effective and do offer protection against the disease. Since no stand-alone preparation of wP vaccine is available in the market, it is not advisable to administer too many doses of pertussis-containing combo products (that usually also contain diphtheria and tetanus toxoids) that may inadvertently enhance the frequencies of undesirable adverse events associated with their use.

H. Pentavalent (DTwP+Hib+Hepatitis-B) vaccine

There are concerns amongst pediatricians related to the quality, suitability and preference of available different wP-vaccine containing pentavalent vaccines in the market since the publication of IAP recommendations on pertussis immunization [9]. Intensive marketing strategies of vaccine manufacturers have further aggravated this confusion. There are no data on either efficacy/effectiveness of individual wP product or comparative evaluation of different available wP combinations in Indian market. ACVIP has urged the National Regulatory Authority (NRA) to setup indigenous National guidelines to manufacture and market different pertussis vaccines in the country [27]. In this background, the committee reviewed the evidence related to available wP-based pentavalent combinations in the country. There are currently six different brands available in Indian market (Table II). All pentavalent vaccines, except Quinvaxem-TM contain PRP-T as carrier protein conjugated with Hib PRP antigen whereas CRM-197 is used in the latter. Both these carrier proteins are consistently highly immunogenic after completion of three primary doses in infants [28-31]. Similarly, no statistically significant difference was found in the safety profile of Hib vaccines containing these two carrier proteins after completion of three doses [28]. Regarding the adjuvant, all the pentavalent products contain Aluminium phosphate in a WHO-prescribed quantity (<1.25 mg) [32]. All the pentavalent combinations, except Quinvaxem, contain thiomersal as preservative. Even the latter also has traces of thiomersal as residue. The committee supports the WHO policy on this issue which continues to recommend the use of thiomersal in vaccines used for global immunization programs since the benefits of using such products far outweigh any theoretical risk of toxicity [32,33].

All the brands are approved by Indian National Regulatory Authority (NRA), Central Drugs Standard Control Organization (CDSCO), MoHFW, GoI after reviewing their phase III clinical immunogenicity and safety studies. However, only the trials of Pentavac, Shan5 and Quinvaxem are published in peer-reviewed journals and available in public domain [34-36]. Information about other brands (Easyfive-TT, Comvac-5, and ComBEfive) are obtained through clinical trial data submitted to CDSCO and package inserts [37-40].

Efficacy: Though direct comparisons are not possible – due to differences in data collection, assays used for evaluation of the immune response, and analysis methods – the seroconversion rates for all the five antigens except for pertussis antigen (which were found lower for Comvac5 and Easyfive-TT) were comparable for all the six brands (Table II). However, the seroconversion rates of Comvac5 and Easyfive-TT against pertussis were comparable to the comparator vaccines’ arms. It has to be noted that till date no known single correlate of protection for pertussis exists, nor any established protective antibody levels are known. Antibody responses to pertussis antigens are variable amongst wP vaccines, likely related to the variability of antigen content amongst them. Furthermore, many different assays are used by manufacturers for the assessment of the immunogenicity.

Reactogenicity: Regarding reactogenicity profile of available brands, a marked diversity was noted. Pentavac was found to be the most reactogenic while Quinvaxem the least. However, it is to be noted that no comparator vaccine was used in Indian trial of Quinvaxem [36] and the reactogenicity profile of the former was found comparable or even superior to the CRM197-based comparator (Easyfive) vaccine (34). Similarly, in the case of Easyfive-TT, the test vaccine fared equally well to the comparator vaccine (Tritanrix+Hiberix) as far as reactogenicity profile is concerned [38,39]. Further, they did not provide information regarding the number of subjects having fever >38ºC. There is no study where all these products are compared ‘head-to-head’ with each other at the same time. On the other hand when one product was compared with another, they fared comparably well against each other. Hence, the committee concludes that all the available pentavalent products are comparable as far as immunogenicity and reactogenicity profile are concerned.

There is no efficacy, effectiveness or post-marketing surveillance (PMS) study from India available in public domain for any of these pentavalent products. There is a large PMS adverse event surveillance study of around 3000 children from Guatemala for Quinvaxem [41].

WHO pre-qualification and world-wide usage: All the products except Comvac-5 are now WHO prequalified [42]. While the Quinvaxem (since 2006), Pentavac (since 2010), and ComBEfive (since 2012) have never been delisted since attaining pre-qualification, the Easyfive-TT (2011-12) and Shan5 (2010-2013) had to be delisted after attaining this status for variety of reasons. Quinvaxem is the most widely used pentavalent vaccine with >400 million doses used globally [43].

The wP vaccines are standardized by protection in the ‘mouse cerebral test’, not by specific antigen content. The committee acknowledges the fact that the process for standardization of quality and efficacy of pertussis vaccines is challenging. Since randomized controlled studies of protective efficacy are no more permitted now owing to ethical and logistic reasons, the post-marketing surveillance and population-based ‘vaccine effectiveness studies’ assume great significance. WHO has made it mandatory to conduct periodic post-marketing surveillance of any newly launched wP based product to monitor its safety since limited safety data are obtained in pre-licensure studies [32].

WHO pre-qualification guidelines for a new wP vaccine, or a new formulation, require proof of concept in a relevant animal model in terms of both potency and safety. The NRAs are guided to ensure potency and safety of a new wP vaccine in preclinical evaluation through ‘intracerebral mouse protection test’ and ‘mouse weight gain test’ before granting clinical testing of a new wP vaccine containing product [32]. Regarding clinical evaluation, determination of antibody response to individual, specific antigens (at least one assay used should determine antibodies against pertussis toxin) is recommended rather than the measurement of antibodies against whole cell or whole cell extracts. The WHO uses very stringent protocol for awarding pre-qualification status to a wP vaccine product [44]. They issue guidelines to NRAs to ensure their application while licensing a wP- based combination in a country. Hence, achieving WHO pre-qualification assumes a very high significance as far as potency, efficacy and safety of any wP based product is concerned. The ACVIP also acknowledges that achieving WHO pre-qualification, which is a dynamic ongoing process with periodic assessment, is a must for all these products to achieve the committee’s approval.

Cost: All the currently available liquid pentavalent combinations cost around INR 600, except Quinvaxem which is around 2.5 times more expensive (Table II). The committee thinks the price of the product cannot be justified considering all the attributes and performance.

Major Changes in Recommendations for IAP Immunization Timetable,  2014

Measles and MMR immunization
• Two doses of MMR at 9 and 15 months
• No stand alone measles dose at 9 months
• No MMR at 4-6 years of age
Typhoid immunization
• Slot for ‘typhoid conjugate vaccine’ for primary immunization at 9-12 months of age
• Recommendation applicable only for Typbar-TCV
• Booster of either Typbar-TCV or Vi-polysaccharide (Vi-PS) vaccine at 2 years of age
• Typhoid revaccination every 3 years, if Vi-polysaccharide vaccine is used
• Need of revaccination following a booster of Typbar-TCV not yet determined
Hepatitis-A immunization
• Single dose administration of live attenuated H2 strain hepatitis A vaccine at 12 months
• Previous recommendations of two-dose is now scrapped 
• Two doses for inactivated (killed) Hepatitis-A vaccine
Human Papillomavirus (HPV) vaccination
• Two doses of HPV vaccine for adolescent/preadolescent girls aged 9-14 years
• For two-dose schedule, the minimum interval between doses should be 6 months
• Three dose schedule for adolescent girls aged 15 years and older to continue
Rabies immunization
• Two new situations, children having pets in home and  children perceived with higher threat of being bitten by dogs to be included in ‘high-risk category of children’ for rabies vaccination
• These groups of children should now be offered ‘pre-exposure prophylaxis’ against rabies
Pertussis immunization
• No change in pertussis immunization recommendations of 2013
• No need of repeating/giving additional doses of wP vaccine to children who had earlier completed their primary schedule with aP vaccine-containing products
• Review and recommendations on the currently available wP vaccine containing pentavalent (DTwP+Hib+ Hepatitis-B) products in Indian market
Other changes
• A brief update and recommendation on use of new Indian Rotavirus vaccine, 116E
• The comments and footnotes for several vaccines are also updated and revised

 

Conclusions: The ACVIP concludes that all the available liquid pentavalent combinations satisfy the licensing criteria set by the Indian NRA and fulfills the requirement of WHO prequalification, except Comvac-5. There is nothing to choose between these products as far as their composition, efficacy and reactogenicity profiles are concerned. However, the lack of published studies on immunogenicity and safety of Comvac-5 and Easyfive-TT, and non-attainment of WHO pre-qualification by the former are indeed source of concern to the committee. Although, Quinvaxem has got highest experience as far as worldwide usage is concerned, the committee believes the product is definitely overpriced. There is an urgent need of conducting large scale PMS studies on the safety and effectiveness of these products in India. The committee urges the CDSCO, MoHFW, GoI to issue notices to the manufacturers to conduct, generate and submit data through PMS studies on the safety and effectiveness of their products.

Funding: None; Competing interests: None stated.

IAP Advisory Committee on Vaccines & Immunization Practices, 2013-14: Office-bearers: CP Bansal (Chairperson), Rohit Agarwal (Co-chairperson), Vijay Yewale (Co-chairperson), Vipin M Vashishtha (Convener), Pravin J Mehta (lAP Coordinator), Members: Shashi Vani, Anuradha Bose, Ajay Kalra, AK Patwari, Surjit Singh; Consultants: Naveen Thacker, NK Arora, Rajesh Kumar, HPS Sachdev, VG Ramchandran, Ajay Gambhir; Rapporteur: Panna Choudhury.

Special invitees: Maharaj Kishan Bhan (Ex-secretary, DBT, GoI, New Delhi), Monjori Mitra, (Institute of Child Health, Kolkata), Sangeeta Yadav (Maulana Azad Medical College, New Delhi), Jyoti Joshi Jain (Immunization Technical Support Unit, MoH& FW, Public Health Foundation of India)

References

1. Indian Academy of Pediatrics Committee on Immunization (IAPCOI). Consensus recommendations on immunization and IAP immunization timetable 2012. Indian Pediatr. 2012;49:549-64.

2. Vashishtha VM, Choudhury P, Bansal CP, Yewale VN, Agarwal R. editors. IAP Guidebook on Immunization 2013-2014. National Publication House, Indian Academy of Pediatrics, Gwalior, 2014.

3. Vashishtha VM, Yewale VN, Bansal CP, Mehta PJ. IAP perspectives on measles and rubella elimination strategies. Indian Pediatr. 2014;51:719-22.

4. Schoub BD, Johnson S, McAnerney JM, Wagstaff LA, Matsie W, Reinach SG, et al. Measles, mumps, and rubella immunization at nine months in a developing country. Pediatr Infect Dis J. 1990;9:263-7.

5. Singh R, John TJ, Cherian T, Raghupathy P. Immune response to measles, mumps and rubella vaccine at 9, 12 & 15 months of age. Indian J Med Res. 1994; 100:155-9.

6. Forleo-Neto E, Carvalho ES, Fuentes IC, Precivale MS, Forleo LH, Farhat CK. Seroconversion of a trivalent measles, mumps, and rubella vaccine in children aged 9 and 15 months. Vaccine. 1997;15:1898-901.

7. Yadav S, Thukral R, Chakarvarti A. Comparative evaluation of measles, mumps and rubella vaccine at 9 & 15 months of age. Indian J Med Res. 2003;118:183-6.

8. Goh P, Lim FS, Han HH, Willems P. Safety and immunogenicity of early vaccination with two doses of tetravalent measles-mumps-rubella (MMRV) vaccine in healthy children from 9 months of age. Infection. 2007;35:326-33.

9. Indian Academy of Pediatrics, Advisory Committee on Vaccines and Immunization Practices (ACVIP), Vashishtha VM, Kalra A, Bose A, Choudhury P, Yewale VN, et al. Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years, India, 2013 and updates on immunization. Indian Pediatr. 2013;50:1095-108.

10. Bhave S, Bavdekar A, Madan Z, Jha R, Bhure S, Chaudhari J, et al. Evaluation of immunogenicity and tolerability of a live attenuated hepatitis A vaccine in Indian children. Indian Pediatr. 2006;43:983-7.

11. Faridi MM, Shah N, Ghosh TK, Sankaranarayanan VS, Arankalle V, Aggarwal A, et al. Immunogenicity and safety of live attenuated hepatitis A vaccine: A multicentric study. Indian Pediatr. 2009;46:29-34.

12. World Health Organization. WHO position paper on hepatitis A vaccines – June 2012. Wkly Epidemiol Rec. 2012;87:261-76.

13. Ali SA, Kazi M, Cortese M, Fleming J, Parashar U, Jiang B, et al. Impact of Different Dosing Schedules on the Immunogenicity of the Human Rotavirus Vaccine in Children in Pakistan – a Randomized Controlled Trial (Abstract). Proceedings of the Vaccine for Enteric Disease. 2013 Nov 6-8; Bangkok, Thailand.

14. Armah G, Lewis K, Cortess M, Parashar U, Ansah A, Gazley L, et al. Immunogenicity of the Human Rotavirus Vaccine Given on Alternative Dosing Schedules in Rural Ghana. Proceedings of the Vaccine for Enteric Disease. 2013 Nov 6-8; Bangkok, Thailand.

15. Bhandari N, Sharma P, Taneja S, Kumar T, Rongsen-Chandola T, Appaiahgari MB, et al. A dose-escalation safety and immunogenicity study of live attenuated oral rotavirus vaccine 116E in infants: A randomized, double blind, placebo-controlled trial. J Infect Dis. 2009;200: 421-9.

16. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: A randomised, double-blind, placebo-controlled trial. Lancet. 2014 Mar 11 [E-pub ahead of print].

17. Sudarshan MK, Madhusudana SN, Mahendra BJ, Rao NS, Ashwath Narayana DH, Abdul Rahman S, et al. Assessing the burden of human rabies in India: results of a national multi-center epidemiological survey. Int J Infect Dis. 2007; 11:29-35.

18. World Health organization. Rabies vaccines: WHO position paper. Wkly Epidemiol Rec. 2010;85:309-20.

19. Bhutta ZA, Capeding MR, Bavdekar A, Marchetti E, Ariff S, Soofi SB, et al. Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomized observer-blind, age de-escalation, phase 2 trials. Lancet Infect Dis. 2014;14:119-29.

20. World Health Organization. Summary of the SAGE April 2014 Meeting. Available from: http://www.who.int/immunization/sage/meetings/2014/april/report_ summary_april_2014/en/. Accessed June 15, 2014.

21. World health Organization. Evidence Based Recommendations on Human Papilloma Virus (HPV) Vaccines Schedules. Background paper for SAGE discussions, March 11, 2014. Available from: http://www.who.int/immunization/sage/meetings/2014/april/1_HPV_Evidence_based_recommendationsWHO_with_ Appendices2_3.pdf?ua=1. Accessed June 15, 2014.

22. D’Addario M, Scott P, Redmond S, Lowet N. HPV vaccines: Review of alternative Vaccination Schedules: Preliminary Overview of the Literature. University of Bern, Bern, Switzerland. Report to WHO 3rd March 2014 (unpublished).

23. European Medicines Agencies, Committee for Medicinal Products for Human Use (CHMP), Assessment report-Cervarix, EMA/789820/2013, 21 November 2013. Available from: htpp://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Assessement Report –Variation/human/000721/WC500160885.pdf. Accessed June 30, 2014.

24. Sankaranarayanan R. Two vs three doses HPV vaccine schedule: low- and middle-income countries, in Eurogin 2013 International Multidisciplinary Congress. 2013: Florence, Italy.

25. Sankaranarayanan R. Trial of two versus three doses of Human Papillomavirus (HPV) vaccine in India. 2013 [cited 2013 Nov 15]; Available from: http://clinicaltrials. gov/show/NCT00923702. Accessed July 4, 2014.

26. Sankaranarayanan R, Evaluation of fewer than three doses of HPV vaccination in India, in WHO Consultation Meeting. 2013: WHO, Geneva.

27. Vashishtha VM, Bansal CP, Gupta SG. Pertussis vaccines: Position paper of Indian Academy of Pediatrics (IAP). Indian Pediatr. 2013; 50:1001-9.

28. Decker MD, Edwards KM, Bradley R, Palmer P. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr. 1992; 120:184-9.

29. Knuf M, Kowalzik F, Kieninger D. Comparative effects of carrier proteins on vaccine-induced immune response. Vaccine. 2011; 29:4881-90.

30. Granoff DM, Anderson EL, Osterholm MT, Holmes SJ, McHugh JE, Belshe RB, et al. Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants. J Pediatr. 1992;121:187-94.

31. American Academy of Pediatrics Committee on Infectious Diseases: Haemophilus influenzae type b conjugate vaccines: Recommendations for immunization with recently and previously licensed vaccines. Pediatrics. 1993; 92:480-8.

32. World Health Organization, WHO Technical Report Series No 941, 2007. Annex 6 Recommendations for whole-cell pertussis vaccine. Available from: http://www.who.int/biologicals/publications/trs/areas/vaccines/whole_cell_ pertussis/Annex%206%20whole%20cell%20pertussis. pdf. Accessed July 7, 2014.

33. World Health Organization. Vaccines and biologicals: Recommendations from the Strategic Advisory Group of Experts. Wkly Epidemiol Rec. 2002; 37:306.

34. Sharma H, Yadav S, Lalwani S, Gupta V, Kapre S, Jadhav S, et al. A phase III randomized, controlled study to assess the immunogenicity and tolerability of DTPw-HBV-Hib, a liquid pentavalent vaccine in Indian infants. Vaccine. 2011; 29:2359-64.

35. Rao R, Dhingra MS, Bavdekar S, Behera N, Daga SR, Dutta AK, et al. A comparison of immunogenicity and safety of indigenously developed liquid (DTwPHB-Hib) pentavalent combination vaccine (Shan 5) with Easyfive (liq) and TritanrixHB + Hiberix (lyo) in Indian infants administered according to the EPI schedule. Hum Vaccin. 2009;5:425-9.

36. Eregowda A, Lalwani S, Chatterjee S, Vakil H, Ahmed K, Costantini M, et al. A phase III single arm, multicenter, open-label study to assess the immunogenicity and tolerability of a pentavalent DTwP-HepB-Hib vaccine in Indian infants. Hum Vaccin Immunother. 2013;9:1903-9.

37. Phase III Clinical Trial Report of BBIL’s pentavalent vaccine (DTwP-HepB-Hib) Comvac-5, Protocol No.BBIL/010/016.

38. Phase III Clinical Trial Report of Panacea Biotech’s pentavalent vaccine (DTwP-HepB-Hib) Easyfive vaccine.

39. Package Insert (PI) of Easyfive-TT vaccine. Available from: http://www.who.int/immunization_standards/vaccine_quality/pq_269_dtp_hepb_hib_1dose_ panacea_ insert.pdf. Accessed July 7, 2014.

40. Package Insert (PI) of ComBEfive. Available from: http://www.who.int/immunization_standards/vaccine_quality/pq_253_254_DTP_HepB_Hib_liquid_BiolE_PI.pdf. Accessed July 7, 2014.

41. Asturias EJ, Contreras-Roldan IL, Ram M, Garcia-Melgar AJ, Morales-Oquendo V, Hartman K, et al. Post-authorization safety surveillance of a liquid pentavalent vaccine in Guatemalan children. Vaccine. 2013;31:5909-14.

42. World Health Organization. WHO prequalified vaccines. Available from: http://www.who.int/immunization_ standards/vaccine_quality/PQ_vaccine_list_en/en/. Accessed July 12, 2014.

43. Schmid DA, Macura-Biegun A, Rauscher M. Development and introduction of a ready-to-use pediatric pentavalent vaccine to meet and sustain the needs of developing countries–Quinvaxem®: the first 5 years. Vaccine. 2012;30:6241-48.

44. World Health Organization. A System for the Prequalification of Vaccines for UN supply. Available from: http://www.who.int/immunization_standards/vaccine_quality/pq_system/en/. Accessed July 12, 2014.  

 

Copyright © 1999-2014  Indian Pediatrics