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 ~  Abstract
 ~ Introduction
 ~  Currently Availa...
 ~  Expected Pneumoc...
 ~  Effect of Upcomi...
 ~ Challenges Involved
 ~ Conclusion
 ~  References
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  Table of Contents  
SPECIAL ARTICLE
Year : 2019  |  Volume : 37  |  Issue : 2  |  Page : 141-146
 

Pneumococcal conjugate vaccine rollout in India: Expectations and challenges


1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 ICMR-National Institute of Epidemiology, Chennai, Tamil Nadu, India
3 Executive Director, INCLEN Trust International, New Delhi, India
4 Medical Director, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India

Date of Submission31-Aug-2019
Date of Decision27-Oct-2019
Date of Acceptance27-Oct-2019
Date of Web Publication19-Nov-2019

Correspondence Address:
Dr. S Balasubramanian
Department of Paediatrics, Kanchi Kamakoti CHILDS Trust Hospital, 12-A, Nageswara Road, Nungambakkam, Chennai - 600 034, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_19_320

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 ~ Abstract 


India is one among the four Asian countries with the greatest number of deaths due to pneumococcal infection among children under 5 years. pneumococcal conjugate vaccine (PCV) has been introduced in a phased manner in five major Indian states. Ambiguity remains in choosing the appropriate type of PCV and optimum schedule with maximum effectiveness specific for each country. Here, we discuss the evidences with respect to serotype coverage, immunogenicity, reactogenicity and dosage schedule for introduction of PCV13 in India. In addition, the expected PCV impact and the challenges are detailed. PCV13 is expected to provide >75% serotype coverage for invasive pneumococcal disease (IPD) serotypes in Indian children combined with the replacement by nonvaccine serotypes which is unpredictable due to lack of complete data. Nasopharyngeal (NP) surveillance is easy, feasible and can replace IPD surveillance in resource-poor settings. Continuous IPD as well as NP surveillance in all the regions are necessary to assess the impact of PCV in India.


Keywords: Impact assessment, India, invasive pneumococcal disease, pneumococcal conjugate vaccine (PCV), Streptococcus pneumoniae


How to cite this article:
Varghese R, Veeraraghavan B, Jeyaraman Y, Kumar G, Arora NK, Balasubramanian S. Pneumococcal conjugate vaccine rollout in India: Expectations and challenges. Indian J Med Microbiol 2019;37:141-6

How to cite this URL:
Varghese R, Veeraraghavan B, Jeyaraman Y, Kumar G, Arora NK, Balasubramanian S. Pneumococcal conjugate vaccine rollout in India: Expectations and challenges. Indian J Med Microbiol [serial online] 2019 [cited 2019 Dec 14];37:141-6. Available from: http://www.ijmm.org/text.asp?2019/37/2/141/271177





 ~ Introduction Top


Streptococcus pneumoniae is the major cause of pneumonia and other invasive diseases in children <5 years, especially in India associated with high mortality. Impact of pneumococcal conjugate vaccines (PCVs) is greatly affected by the geographical diversity of the serotypes. In addition, India-specific invasive pneumococcal disease (IPD) or pneumococcal serotype data are limited to certain regions raising major challenges in impact assessment. We discuss in present the available evidence and the impact expected from PCV rollout and the challenges involved in the assessment of the impact.


 ~ Currently Available Pneumococcal Conjugate Vaccines Top


Primarily, two PCVs – PCV10 (ten serotypes) and PCV13 (13 serotypes) are recommended by WHO and have been used worldwide.[1] The impact of PCV10 and PCV13 is studied extensively worldwide, and the summary has been submitted by SAGE as PRIME report in 2017.[2] This includes the impact of both PCV10 and PCV13, in disease and carriage, when given as 2p+1 or 3p+0 immunisation schedule.

The difference between PCV10 and PCV13 is only in the antibody levels after the final dose, where 2p+1 schedule is equal to 3p+0 schedule and superior to 3p+1schedule [3] [Table 1] and [Table 2]. Geometric mean opsonization index, that reflects functional antibodies, is higher for serotype 1 than other serotypes in PCV13 after post-primary series and high for all serotypes after post-booster dose [Table 1]. Thus, serotype 1 is highly protected at the early age by PCV13. For serotype 6B, higher geometric mean concentration (GMC) is seen after post-primary series for PCV10 and post-booster for PCV 13. Therefore, the period of low antibody concentration of 6B, post primary, when given as 2p+1 schedule can be reduced by introducing the booster early at 9 months. Therefore, PCV10 and PCV13 are equally immunogenic when given as 2p+1 and 3p+0 schedule for the common nine serotypes. PCV13 has additional advantage of serotype-specific protection in carriage as well as IPD for the non-PCV10 serotypes in PCV 13. Cross protection for IPD by PCV 10 is only for 6A but not for 19A and has no effect on carriage. In India, serotype 14, 1, 19F, 6B, 5, 23F, 9V, 19A and 6A constitute the major IPD serotypes in children [Figure 1]. Therefore, PCV13 is presumed to give increased serotype coverage and better protection early at the 1st year of life when given in 2+1 schedule.
Table 1: Effectiveness of pneumococcal conjugate vaccine 13 (2p+1) against pneumococcal conjugate vaccine 10 (2p+1 and 3p+0, 3p+1)

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Table 2: Importance of recommended pneumococcal conjugate vaccine immunization schedules and their observations

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Figure 1: Invasive pneumococcal serotype distribution from 2008 to 2019 in Indian children

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In developing countries, optimum schedule is chosen that favours maximum protection in highest susceptible age group, combined with the routine vaccination schedule and with minimum doses to ensure maximum coverage and affordability. In India, the PCV schedule chosen is 2 primary doses and one booster at 9th month to increase the protective immunity in the 1st year of life because the target group for IPD with high mortality is children <2 years.

The additional advantage of the booster doses is reduction in the carriage which is important to reduce transmission (herd immunity). A new strategy targeting to enhance the herd immunity was initiated in Cuba: first, a single dose (0+1) of PCV is given to 1–5 years [4] and second, 1+1 schedule at infancy and 9 months takes care of the vulnerable population. This Cuban strategy is expected to decrease the number of doses without compromising the effectiveness in resource-poor settings. The outcome of this will help guide in decision-making for newer vaccines.


 ~ Expected Pneumococcal Conjugate Vaccine Impact in India Top


India and the three neighbouring countries in Asia were among the top four countries with the greatest number of pneumococcal deaths due to pneumococcal infection among children under 5 years.[5] Recently, modelled estimates for 2015 reported the national mortality rates in children aged 1–59 months as 56/100,000 for pneumococcal infection with highest numbers in Uttar Pradesh and Bihar and 1.6 million cases of severe pneumococcal disease, of which pneumococcal pneumonia accounts for more than 97%.[6] With increased evidences on high morbidity and mortality due to S. pneumoniae, combined with the high prevalence of PCV 13 serotypes in under-five children led to the introduction of PCV13 in five Indian states, namely Himachal Pradesh, Haryana, Uttar Pradesh, Madhya Pradesh and Bihar, in 2017.

'Impact' quantifies the reduction of target disease in the entire population after implementation of vaccination, and it is a combination of vaccine effectiveness, population coverage and herd effect. The indirect effect or herd effect is due to reduced transmission of the target disease in the community due to the vaccinated group in the population. The impact of PCV is measured using endpoints such as IPD, pneumonia, acute otitis media (AOM), nasopharyngeal (NP) carriage and mortality [7] in vaccinated and the unvaccinated group of all ages [Figure 2]. Among these, IPD is the gold standard since it involves assessment of serotype specific effectiveness, serotype replacement and herd immunity. Proving pneumococcal aetiology of pneumonia and AOM is challenging due to difficulty in diagnosis. Therefore, pneumococcal carriage serves as a surrogate marker to determine vaccine impact because the absence of vaccine type (VT) serotype colonised in the NP carriage of vaccinated indicates the direct effect and the same in unvaccinated indicates herd immunity.
Figure 2: Direct and indirect effects of pneumococcal conjugate vaccine on disease and non-disease endpoints. IPD: Invasive pneumococcal disease, NP: Nasopharynx, VT: Vaccine type, NVT: Non-vaccine type

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Effectiveness in children

Based on the cumulative serotype distribution inclusive of IBIS, BASIS, ASIP and PIDOPS [Figure 1], PCV13 is expected to provide higher serotype coverage of 77% against the serotypes responsible for IPD in Indian children <5 years.[8],[9],[10] The non-vaccine serotypes causing IPD is around 20%–25% throughout the years. Recently, increasing penicillin resistance in meningeal isolates is a major concern in India.[11] 75% of the resistant serotypes were 14, 19F, 6B, 6A and 23F which are of PCV13 serotypes. Therefore, PCV13 is presumed to give increased serotype coverage and reduce antimicrobial resistance against IPD serotypes in India.

PCV13 is found to be highly beneficial for bacteraemic pneumonia with serotype coverage of 64%, whereas in non-bacteraemic pneumonia, the serotype coverage is only 34%.[12] An increased reduction of CAP due to PCV was also reported in children <5 years. Reduction in AOM caused by VT pneumococci results in increase of other AOM pathogens. However, there have been studies proving prevention of AOM by PCV13 serotypes [13] and those of showing overall reduction of AOM by 6%–7% with PCV7.[14],[15]

As discussed above, based on the evidence from PCV impact studies in other countries, 2p+1 is superior to 3p+1 in reducing the colonisation of VT serotypes and the antibody production. The current IAP (Indian Academy of Pediatrics) guidelines consist of 3p+1 schedule, three primary doses at 6, 10 and 14 weeks followed by booster at 15 months.[16] Shifting to 2p+1 schedule, with booster at 9 months, will provide better protection. This also reduces the cost burden by decreasing the number of doses. As part of Tamil Nadu innovation initiatives (2018–2019) National Health Mission, Tamil Nadu has introduced administration of PCV13 to preterm very low birth weight babies discharged from special new born care units. This is to reduce the post neonatal mortality rate caused by pneumonia, which is currently 17%.[17],[18]

In addition, catch-up vaccination can be given targeting the vaccine non-eligible (or non-cohort) children. Catch-up vaccination can be introduced along with new vaccination schedule so as to accelerate herd protection. Two catch-up doses at an interval of at least 2 months apart are recommended to children 12–24 months of age and 2–5 years of age at high risk for pneumococcal infection. Two doses are more immunogenic and produce higher response than single dose for serotypes 6B, 23F and for 19A when using PCV10. Considerably, PCV13 with a single-dose catch-up schedule produces higher antibody response in children at 12–48 months of age, compared to PCV10. As an indirect effect of catch-up program, significant reduction in the VT carriage in the population was observed in the 2nd year following vaccine introduction in Kenya.[19]

Effectiveness in the elderly

Reduction in carriage of vaccine serotypes renders indirect effect or herd immunity in the elderly. PCV13 reduces carriage of serotypes 6A and 19A but PCV10 does not eliminate the colonisation. In addition, increase in the carriage of non-vaccine serotypes replacing the VTs is also observed. Studies in Belgium, Sweden and Norway observed increase in IPD due to non-vaccine serotypes in the elderly after PCV introduction.[20],[21],[22] Countries using PCV10 witnessed increase in IPD caused by 19A and 6C and countries using PCV13 reported increase in non-VTs excluding 6C because of cross protection for 6A by PCV10 and 6C by PCV13. Persistence of IPD by 4, 19F and 19A in elderly after initial reductions was seen in Germany without any herd protection for serotype 3. Thus, the expanding non-vaccine serotypes limit the effect of current vaccines against IPDs in the elderly.

In India, among the elderly, the most common serotypes are 3, 14, 19F, 7F, 8, 1, 6A, 19A, 4, 23F and 5 which are predominantly PCV13 serotypes. Thus, PCV13 is expected to provide 70% of serotype coverage of IPD serotypes in the elderly compared to PCV10 which is only 43%.[23] Surprisingly, PPSV23 provides only 3% increased serotype coverage than PCV13. Therefore, in the elderly (≥65 years), PCV13 provides long-term immunity and similar serotype coverage compared to PPV23 in India (PCV 13%–70% and PPV 23%–73%). All the elderly should be compulsorily vaccinated by PCV13. The current recommendation of ≥1-year time period between the two (PCV13 and PPV23) vaccines should be followed. Augmented response to PPSV23 is observed when it is administered following the initial administration of PCV13,[24] whereas there is a reduced response while administered vice versa. However, PPV23 is not good for herd immunity because of the following reasons: (1) it is less immunogenic, (2) it does not produce mucosal immunity, (3) it may induce hyporesponsiveness with repeat booster doses and (4) there is no effect on colonisation or carriage, and hence, it does not prevent community acquired or non-bacteraemic pneumonia.


 ~ Effect of Upcoming Vaccines With Additional Serotypes Top


Currently available vaccines do not cover more than 70%–80% IPD serotypes in all countries due to the geographical serotype diversity. Reduction in vaccine serotypes after vaccination has led to increase in non-vaccine serotypes (serotype replacement). Customising country-specific vaccines by including additional serotype (increasing the valency) is expensive and attaining similar immunogenicity for all serotypes is uncertain. Newer strategies such as removing the least prevalent serotypes from the existing vaccines and adding the important ones are under trials.[25] There are four next generation vaccines under development of which three are higher valency vaccines [Table 3]. Serotype 3 is responsible for half of the 3% decreased coverage of new PCV10 compared to PCV13. However, there is no documented evidence for protection conferred by serotype 3. Therefore, the new PCV10 can be used at a cheaper price while attaining the percentage coverage similar to PCV13. In the adults and elderly, all the newer vaccine gives more or less the same coverage since the newer additional serotypes are present only few numbers in India. Hence, the modified 10 valent may be cost-effective and appropriate in Indian settings compared to the newer high-valent vaccines.
Table 3: Serotypes included in the newer vaccines and percentage serotype coverage in India

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 ~ Challenges Involved Top


Both pre-PCV and post-PCV surveillance strategies are associated with challenges. The main challenges are associated with IPD and impact assessment which are detailed in [Table 4].
Table 4: Invasive pneumococcal disease and impact assessment challenges in India

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 ~ Conclusion Top


PCV13 is expected to provide >75% serotype coverage of IPD serotypes in Indian children. NP surveillance for S. pneumoniae should be encouraged to replace IPD surveillance in resource-poor settings. Sustained and efficient IPD as well as NP surveillance systems uniformly in all the regions are necessary to assess the true impact of PCV in India. Studies on impact from pneumococcal vaccination are urgently needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 ~ References Top

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Linares-Pérez N, Toledo-Romaní ME, Santana-Mederos D, García-Fariñas A, García-Rivera D, Valdés-Balbín Y, et al. From individual to herd protection with pneumococcal vaccines: The contribution of the Cuban pneumococcal conjugate vaccine implementation strategy. Int J Infect Dis 2017;60:98-102.  Back to cited text no. 4
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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