Pediatric Infectious Disease 2012 JulyeSeptemberVolume 4, Number 3; pp. 112e124 Review Article

Key statements of IAPCOI and IAP Immunization Timetable for year2012

Vipin M. Vashishtha*

NationIndia.*Tel.: þAvailaCopyrihttp://d

ABSTRACT

Vaccinology today is a rapidly changing specialty of medical science where new developments are regularly takingplace at short intervals. There is a need to review/revise recommendations about existing vaccines in light of recentinformation. Following an IAPCOI meeting in December 2011, a draft statement was prepared and circulated amongthe meeting participants to arrive at a consensus.

Objectives: To review and issue recommendations on the recent contentious issues pertaining to rotavirus, Hib, andpneumococcal conjugate vaccines and to revise recommendations for 2012 Immunization timetable for pediatriciansin office practice.

Recommendations: IAPCOI abolished the earlier categorization of vaccines in four categories. On rotavirus, thecommittee stresses the need of having more data on disease burden in India. Further, there is a need to optimize useof rotavirus vaccines in India to achieve higher yields in term of protective efficacy. In the want of adequate data, thecommittee is not able to issue any specific recommendation on the suitability of a particular rotavirus vaccine(monovalent Vs multivalent) for the country. The committee also acknowledges a small risk of acute intussusceptionsfollowing use of current generation of rotavirus vaccines and recommends inclusion of the history of intussusceptionin the past as an absolute contraindication. The committee concludes there is no safety concerns of Hib vaccines asreported frequently in lay media. On the disease burden of pneumococcal diseases (PD), the committee concludesthat there is need of conducting more community based studies to gather more evidence. Similarly, the data onprevalence of different pneumococcal serotypes in the country is sparse and limited to few hospital based studies.There is need of establishing real-time multi-site pneumococcal disease surveillance in the country. Due to scarcity ofdata on the prevalence of pneumococcal serotypes and non-typeable hemophilus influenzae (NTHi) in India, it isdifficult to comment on the superiority of one pneumococcal conjugate vaccine over other. The committee alsorevised the recommendations for the year 2012.

Copyright © 2012, Indian Pediatrics

Keywords: India, Indian Academy of Pediatrics, Committee on Immunization, Recommendations

Open access under CC BY-NC-ND license..

ROTAVIRUS VACCINE

Efficacy of current rotavirus vaccines in India

There are no efficacy trials of the licensed rotavirusvaccines available in India. The data from other developing

al Convener, IAP Committee on Immunization, 2011-13, Mangla Hosp

91 1342 262931, þ91 98370 95664 (mobile), þ91 97596 41900 (mble online: 10.9.2012ght � 2012, Indian Pediatricsx.doi.org/10.1016/j.pid.2012.08.001

. Open access under CC BY-NC-ND licens

countries shows efficacy ranging from 17.6% (in Mali) to61.2% (in South Africa and Malawi).1e5 There is definitegradient in the efficacies of these vaccines when differentregions of the world are compared e highest in US andEurope, moderate in Latin America, and low in Africaand Asia.1e8 IAPCOI still believes that in developing

ital & Research Center, Shakti Chowk, Bijnor 246701, Uttar Pradesh,

obile); fax: þ91 1342 265102, email: vipinipsita@gmail.com

e.

Key statements of IAPCOI and IAP Immunization Timetable Review Article 113

countries with high rotavirus disease incidence, evenmoderate to low vaccine efficacy translates into significantnumbers of severe rotavirus gastroenteritis cases preventedand into significant public health impact. More rotavirusdisease burden may be prevented in developing countriesdespite lower vaccine efficacy than in countries with lowrotavirus disease burden and higher vaccine efficacy.9

However, considering that oral vaccines elicit diminishedimmune responses or have lower efficacy in developingcountries than in developed countries,10 and since India ishaving history of poor performance of other oral vaccines,notably OPV in recent past,11e13 it would not be prudent to

extrapolate data from other countries having comparableepidemiologic, economic, and demographic indices.

Administration schedule of rotavirus vaccines inIndia

In a recent community-based study from Vellore, it wasnoted that rotavirus infection generally occurred early inlife, levels of re-infection were high and even three naturalinfections were able to provide only 79% protection againstmoderate or severe disease, with no evidence of homotypicprotection as believed so far.14 Therefore, there may be

114 Pediatric Infectious Disease 2012 JulyeSeptember; Vol. 4, No. 3 Vashishtha

Key statements of IAPCOI and IAP Immunization Timetable Review Article 115

a need for modification of the rotavirus vaccination strategyin India, by increasing the dose or increasing the number ofdoses or delaying the doses or even considering neonatalimmunization. These considerations were further supportedby the immunogenicity study of another live attenuatedhuman oral rotavirus vaccine 116E in Indian infants, whereadministration of higher (1 � 104 ffu vs 1 � 105 ffu) andmore frequent (2 vs 3) doses resulted in more robust immuneresponses.15 Consequently, the ongoing phase III efficacytrial with this strain is conducted with higher dose (105 ffu)and a 3-dose schedule (6, 10 and 14 weeks).15 It can beargued that one study in South Africa and Malawi withmonovalent rotavirus vaccine (RV1, marketed as Rotarix)did not detect significant differences in vaccine immunoge-nicity or efficacy on pooled analysis between the cohort

receiving two vaccine doses and the cohort receiving threedoses.3 However, there was a slight but non-significant trendtoward higher seroconversion rates and vaccine efficacy withthe three-dose schedule, and these differences were moremarked in South Africa (81.5 (55.1e93.7) vs 72.2(40.4e88.3)) than in Malawi (49.7 (11.3e72.2) vs 49.2(11.1e71.7)).3 The two-dose schedule used in this trialwas 10 and 14 weeks instead of 6 and 10 weeks.3

Administering rotavirus vaccines at younger ages couldfurther lower the immunogenicity of the vaccines, becauseof the potential for greater interference of maternal antibodyand enhanced replication of the oral poliovirus vaccine.3

In the above African study with RV1, the researchersaccepted that the study was not powered to detect differ-ences in dose schedule.3 Furthermore, there have been

116 Pediatric Infectious Disease 2012 JulyeSeptember; Vol. 4, No. 3 Vashishtha

low seroconversion rates (58.3%; 95% CI: 48.7; 67.4) withtwo doses of RV1 in comparison with three-dose scheduleof RV5 (82.4% (CI; 75; 90%)) and 116E (89.7% (42.4;80.6%)) in immunogenicity studies in India.15e17 In theRV1 trial, the first dose was administered between 8 and10 weeks (mean age e 8.7 weeks) and the second dosebetween 12 and 16 weeks (mean age e 13.4 weeks).16

Hence, there is no immunogenicity data for 6 and 10 weeksadministration or data on interference with simultaneousOPV administration from India. It is important when exam-ining immunogenicity data to point out that although sero-conversion is not a direct proxy for efficacy, it doesdemonstrate that the virus is able to colonize the infantgut and induce a robust immune response.

Key statements of IAPCOI and IAP Immunization Timetable Review Article 117

According to the WHO Ad-hoc Group of Experts onrotavirus vaccines,18 most countries with high rotavirus

disease incidence or high under-5 mortality rates (wherechildren would particularly benefit from robust protectionfrom rotavirus infection) have 6, 10, 14 week EPI sched-ules. If rotavirus vaccines are to be co-administered withOPV in a setting with an EPI vaccination schedule begin-ning at 6 weeks of age, the second dose of RV1 may notbe sufficient to provide adequate immunity against severerotavirus disease.18 A 2-dose schedule at 10 and 14 weeksis also assumed to be programmatically problematic, sincethis would likely result in a failure in administration ofthe full course of vaccines to children in developing coun-tries due to the restrictive upper age limit for rotavirusvaccine administration, resulting from the approach ofattempting to avoid administration of rotavirus vaccinesduring the ages when there is a heightened risk of intussus-ceptions.18 After debating intensely, the committee thinksthat there is a need to seriously relook at the proper admin-istration schedule of rotavirus vaccines in India in order toachieve higher yields in term of protective efficacy.

Safety of rotavirus vaccines and post-marketingsurveillance data on acute intussusceptions inIndia

The committee reviewed the emerging data on intussuscep-tion related to current rotavirus vaccines following large-scale use of these vaccines in Mexico, Brazil, Australiaand US.19e22 The post-marketing surveillance (PMS) datafrom India by the manufacturers of two rotavirus vaccineslicensed in India was also reviewed.

Based on PMS data, the current rotavirus vaccines havebeen associated with an increased risk of intussusceptions(about 1e2/100,000 infants vaccinated) for a short periodafter administration of the first dose in some populations.19

This risk is 5e10 times lower than that observed withthe previously licensed vaccine (1 case per 10,000 doses).There are no published reports on incidence/rates ofacute intussusception following rotavirus vaccination inIndia. However, the PMS data (unpublished) of Indianmanufacturers revealed 13 cases of acute intussusceptionsassociated (causality not yet proved) with rotavirusvaccines administration since the launch of RV1 in Indiatill December 2011, and two cases following RV5 duringa five-month surveillance period (MayeSeptember 2011)in India.

There is limited information on the incidence of intus-susception and its risk factors in India. No large-scale trialsof rotavirus vaccines have been conducted in the country toassess whether there is an increased risk of intussusceptionassociated with the vaccination. Data on background rates

of intussusception in developing countries are required tofacilitate informed decision making about use of newrotavirus vaccines. These background rates are also neededfor estimation of the sample size needed for studies todemonstrate safety both before and after licensure of newrotavirus vaccines. Such population-based data are notavailable in most developing countries, including India.However, a recent study from Delhi found the incidenceof intussusception requiring hospitalization was 17.7 casesper 100,000 infant-years of follow-up (95% CI: 5.9e41.4cases per 100,000 infant-years).23 The study also concludedthat natural rotavirus infection did not appear to be a majorcause of intussusception in Indian infants. This incidenceappears to be lower than that reported in other middle-and high-income countries. Another retrospective studyfrom a tertiary-care hospital from south India identified31 children with definite intussusception during the studyperiod of 1 January 2001e30 June 2004.24

After reviewing recent data, the committee concludesthat there is definite albeit a small risk of acute intussuscep-tions following use of current generation of rotavirusvaccines. However, the benefits of rotavirus vaccinationagainst severe diarrhea and death from rotavirus infectionfar exceed the miniscule risk of intussusceptions. It urgesthe manufacturers to actively monitor the risk of intussus-ceptions as the usage of these vaccines is bound to go up.This will also require strengthening of AEFI surveillancein the country. Information about the possible risk of intus-susceptions associated with rotavirus vaccination needs tobe communicated clearly to the national decision-makers,healthcare providers, and parents. The committee alsostresses the need of strictly adhering to the set upper agelimits of these vaccines, i.e. the first dose of either RV1or RV5 should be administered between the ages of 6weeks and 14 weeks and 6 days, and that the maximumage for administering the last dose of either vaccine shouldbe 32 weeks25 of these vaccines while prescribing them inoffice practice. The committee has recommended inclusionof the history of intussusception in the past as an absolutecontraindication for rotavirus vaccine (RV1 and RV5)administration.

PNEUMOCOCCAL CONJUGATE VACCINES

Suitability of PCV13 vs PCV10 for Indian children

The committee studied the recent data on PCV13 andPCV10. The committee also reviewed the reports ofPCV13 studies done worldwide on immune responses(IgG e GMC, OPA e GMT) and boostability for the sero-type 3 capsular antigen,26 and the immune responsesfollowing post-primary and post-booster series against

Recommendations for IAP ImmunizationTimetable, 2012

IAP Immunization Timetable, 2012

Major changes

d Polio: sequential IPV-OPV schedule is recommen-ded for primary polio immunization in place ofcombined OPV þ IPV schedule.

d Hepatitis-B: ‘Birth-6 weekse6 mo’ is recommen-ded as most preferred schedule instead of earlier‘0e6 weekse14 weeks’ schedule.

d Rotavirus: history of intussusception in the past isadded as an absolute contraindication for RVvaccine administration.

d Pneumococcal: prematurity and very-low birthweight are added as another high-risk categoryfor pneumococcal vaccination.

d Influenza: guidelines are provided for influenzavaccination.

118 Pediatric Infectious Disease 2012 JulyeSeptember; Vol. 4, No. 3 Vashishtha

serotype 19A infections, with PCV10 and PCV13.27,28 Ithas reviewed the interim data of COMPAS trial done inthree Latin American countries with PCV1029 and effec-tiveness of PCV10 in Brazil.30

The committee also reviewed available data on the effi-cacy of the new serotypes in the PCV13. In England andWales,31 vaccine effectiveness (VE) for the new serotypesfor 2 doses under a year was 78% (95% CI: �18 to 96%)and 77% (CI: 38e91%) for one dose over a year. VE for7F and 19A was 76% (CI: 21e93%) and 70% (CI:10e90%), respectively for � one dose, for serotypes 1and 3 was 62% and 66%, respectively although confidenceintervals spanned zero. IPD due to PCV13-only serotypeshalved in children under 2 years in the study period.31

The committee believes that the direct protectionrendered by the serotype included in a vaccine formulationis definitely superior to any cross protection offered by theunrelated serotypes even of the same group in a PCV formu-lation. However, the committee still not convinced about theclinical efficacy of serotype 3 contained in PCV13 despitemultiple studies showing good functional immune responsesafter the infant series29 and reasonably good effectiveness.31

There has been no consistent PCV13 impact on serotype 3IPD or carriage reported so far.

Similarly, the committee still thinks that despite usinga different conjugation method (cyanylation vs reductiveamination),32 PCV10 is yet to demonstrate a better clinicalefficacy (cross protection) against serotype 19A than shownby PCV7. Though current seroprevalence of type 19A inIndia is not known, but its presence is confirmed by almostall the recent studies.33e35 Since this serotype is increasingin many other Asian countries and has got higher antimicro-bial resistance characteristics than other serotypes,34,35 thecommittee believes that protection against 19A will be crit-ical to determine which vaccine is appropriate to use in thecountry. Recent data has now shown that PCV13 providesprotection against 19A,31 while it is unknown if the pres-ence of ‘novel’ 19F in PCV10 will provide cross protectionagainst 19A.36 On the other hand, the committee isconvinced about the adequate cross protection renderedby serotype 6Be6A based on performance of PCV7 inmany European countries and US in decreasing IPDscaused by 6A. However, the exact role and significanceof 6C which is clearly emerging as replacement serotypeis yet to be determined.

The committee thinks that though NTHi, a co-pathogenplays some role in the pathogenesis of mucosal disease withStreptococcal pneumoniae, its role in childhood pneumoniais still not proven.

After appraising in detail all the available relevant data,the committee concludes that since there is scarcity of dataon the prevalence of pneumococcal serotypes including

serotypes 3, 6A and 19A, and non-typeable Haemophilusinfluenzae (NTHi) in India, it is almost impossible tocomment on the exact superiority of one product over other.Further, in the absence of head to head trials it is difficult todetermine if either vaccine has a clear advantage over other.Although recent publications37 state that the same few sero-types are responsible for a large proportion of PD in allgeographic regions and new PCVs cover almost 70% ofserotypes prevailing in India, the committee believes thatit is critical to know what percentage of pneumonia, menin-gitis and other IPDs are caused by the pneumococcal sero-types not included in existing formulations.

Recommendations for premature and low birthweight infants

The committee has now stressed the need of treating prema-turity (PT) and very-low birth weight (VLBW) infants asanother high-risk category for pneumococcal vaccination.These infants have up to 9-fold higher incidence of invasivepneumococcal diseases (IPD) in (VLBW babies) ascompared to full size babies.38 The risk ratio for LBWinfants compared with normal birth weight infants was2.6, and for premature infants compared with full-term(FT) infants was 1.6. PCV must be offered to these babieson priority basis. PCV was as immunogenic in LBW andPT as in NBW and FT infants; the vaccine efficacy forboth groups was found 100%.38

Key statements of IAPCOI and IAP Immunization Timetable Review Article 119

The IAPCOI has issued recommendations for the IAPImmunization Timetable for the year 2012 that includesthe following major changes from last year:

Poliovirus immunization

In the light of remarkable achievement in the field of polioeradication in India over the last one year,39 the committeehas now decided to adopt a sequential IPV-OPV schedule.This will pave the way to ultimate adoption of all-IPVschedule in future considering the inevitable cessation ofOPV from immunization schedules owing to its safety issues(VAPP and cVDPVs). This policy is in accordance with therecent decision taken by GPEI where phased removal ofSabin viruses, beginning with highest-risk (type 2) wouldbe undertaken.40 This will result in elimination of VDPVtype 2 in ‘parallel’ with eradication of last wild poliovirusesby switching from tOPV to bOPV for routine EPI andcampaigns. This switch will result in much early introductionof IPV than anticipated, at least in high-risk areas forVDPVs, to provide type 2 protection.40

Why changes in polio immunization schedulebecame inevitable?d India is polio free for >1 year!!d Type 2 WPV eradicated in 1999d cVDPVs especially type 2 is a concernd VAPP cannot be overlooked anymore!d New ‘end game strategy’ announced in November

2011d No preparations for approaching ‘end game’

New poliovirus vaccination scheduleThe primary schedule:

d OPV (birth dose) þ 3 doses of IPV at 6, 10 and 14weeks þ 2 doses of OPV at 6 & 9 months þ IPV at15e18 months (booster) þ OPV at 5 yearsThe alternative schedule:

d OPV at birthþ 2 doses of IPV at 8 and 16 weeks(i.e. 2 & 4 mo) þ OPV at 6 & 9 mo þ IPV at15e18 mo þ OPV at 5 yearsCatch-up schedule (IPV up to 5 years of age):

d IPV can be given as 3 doses; 2 doses at 2 monthsinterval followed by a 3rd dose after 6 months

There is considerable evidence to show that sequentialschedules that provide IPV first, followed by OPV, canprevent VAPP while maintaining the critical benefitsconferred by OPV (i.e. high levels of gut immunity). Datafrom several studies show that sequential schedules consider-ably decrease the risk of VAPP.41e44 There is moderate levelof scientific evidence that sequential immunization schedulesstarting with two or more doses of IPV and followed by twoor more doses of OPV (at an interval of 4e8 weeks) induceprotective immunological responses to all three poliovirusserotypes in �90% of vaccinees.45 However, the committeehas retained the birth dose of OPV as recommended earlier.Providing the first OPV dose at a time when the infant is stillprotected by maternally-derived antibodies may, at leasttheoretically, also prevent VAPP. A birth dose of OPV isconsidered necessary in countries where the risk of polio-virus transmission is high.46

The primary scheduleThe committee recommends birth dose of OPV, threeprimary doses of IPV at 6, 10 and 14 weeks, followedby two doses of OPV at 6 and 9 months, another dose(booster) of IPV at 15e18 months and OPV at 5 years.Alternatively, two doses of IPV can be used for primaryseries at 8 and 16 weeks, though this schedule is immu-nologically superior to EPI schedule and the number ofIPV doses is reduced, but will be more cumbersomedue to extra visits and incompatibility with combinationformulations. Further, the child would be susceptible toWPV infection for the first two months of life consid-ering the epidemiology of WPV in India till quiterecently.

Since IPV administered to infants in EPI schedule (i.e. 6weeks, 10 weeks and 14 weeks) results in suboptimal sero-conversion,46 hence, a supplementary dose of IPV is recom-mended at 15e18 months. IPV should be givenintramuscularly (preferably) or subcutaneously and maybe offered as a component of fixed combinations ofvaccines. However, the committee recommends that ifIPV is unaffordable or unavailable, the primary seriesmust be completed with three doses of OPV given at 6,10, and 14 weeks. No child should be left without adequateprotection against wild poliovirus (i.e. three doses of eithervaccine). All OPV doses (mono-, bi- or trivalent) offeredthrough supplementary immunization activities (SIAs),should also be provided.

Catch-up scheduleIPV may be offered as ‘catch up vaccination’ for childrenless than 5 years of age who have completed primaryimmunization with OPV. IPV can be given as three doses;two doses at two months interval followed by a third doseafter 6 months. This schedule will ensure a long lastingprotection against poliovirus disease.

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Key statements of IAPCOI and IAP Immunization Timetable Review Article 121

Hepatitis-B immunization

The committee has now recommended the followingschedule for routine Hepatitis-B vaccination in office prac-tice for children: the first dose of a three-dose scheduleshould be administered at birth, second dose at 6 weeks,and third dose at 6 months (i.e. 0e6 weeke6 month).This schedule is not only more closer to immunologicallyideal and most widely used 0e1e6 months schedule, butalso confirms to latest ACIP recommendations whereinthe final (third or fourth) dose in the Hepatitis-B vaccineseries should be administered no earlier than age 24 weeksand at least 16 weeks after the first dose.47 It will replacethe existing schedule of 0e6 weeke14-week. However,the Hepatitis-B vaccine may be given through other sched-ules, considering the programmatic implications andlogistic issues. The committee stresses the significanceand need of birth dose.

Influenza vaccination

The committee reviewed the WHO recommendationsregarding composition of flu vaccines for the southernand northern hemisphere for use in the 2012e2013 influ-enza seasons.48,49 For the northern hemisphere, it willcontain the following strains: an A/California/7/2009(H1N1) pdm09-like virus; an A/Victoria/361/2011(H3N2)-like virus; and a B/Wisconsin/1/2010-like virus.48

The last two strains will be different from the last year’svaccine for the region however; there will be no changein the composition of influenza vaccines for the southernhemisphere for 2012.49 Last year, the strains were similar

for both the hemispheres. This will have impact on thetypes of vaccines to be used in coming season.

As far as the influenza virus circulation in India is con-cerned, the data since 2004 suggests a clear peaking of circu-lation during the rainy season across the country e‘JuneeAugust’ in north (Delhi), west (Pune) and east(Kolkata), and ‘OctobereDecember’ in south (Chennai).50

This data is also consistent with theWHO circulation patternsfor 2010 and 2011 for India which also shows a clear peakcoinciding with the rainy season across the country. Thesedata illustrate the difficulty in having effective uniform vacci-nation timing for a vast country like India and have implica-tions when formulating vaccination policies. The evidence ofantigenic drifts of circulating influenza viruses in India,together with the temporal peaks in seasonality of influenzain different parts of the country; illustrate the need for a stag-gered approach in vaccination timing. Hence, the best timefor offering vaccine for individuals residing in southern stateswould be just before the onset of rainy season, i.e. beforeOctober while for rest of the country, it should be beforeJune. Though, the committee acknowledges that this issueis still contentious and unresolved.

This is to be noted that WHO convenes two meetings toprovide recommendations for the usage of influenzavaccine in February and September each year. The vaccinefor the February recommendations (Northern hemisphere)and September recommendations (Southern hemisphere)becomes available after 6 months of each recommendation.With the above background the vaccine that shall be avail-able in MarcheApril 2012 (Southern hemisphere) this yearis based on the recommendation made in September 2011which took into account the data from the past year i.e.

122 Pediatric Infectious Disease 2012 JulyeSeptember; Vol. 4, No. 3 Vashishtha

August 2010eSept 2011 (thus covering India’s rainyseason peak last year from June to August 2011). Whereasthe vaccine that shall be available in August 2012 (Northernhemisphere, with the 2 new strains) shall be based on therecommendation made in February 2012 which took intoaccount the data from the past year i.e. March 2011eFeb2012 which means that by the time it is available in August2012, the most of the country barring southern states mayhave already passed the peak influenza activity.

In addition to this, WHO classifies India under the‘South Asia’ transmission zone of influenza circulation.This along with summary review of the 2011 southernhemisphere winter influenza season49 strongly pointsIndia’s alignment with the availability of Southern hemi-sphere vaccine (MarcheApril) to ensure we have the latestavailable strains for early vaccination to prevent the peak ofcirculation of Influenza in the rainy season across thecountry.

(Abstracted from: Consensus Recommendations onImmunization and IAP Immunization Timetable 2012,Indian Pediatrics, July 2012, Vol: 49, pp: 549e565. Avail-able from: http://www.indianpediatrics.net/july2012/549.pdf Accessed on July 18, 2012.)

CONFLICTS OF INTEREST

The author has none to declare.

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