Introduction of pneumococcal vaccine in national immunisation schedule in India: boon or bane?

Vaccination is undoubtedly one of the most cost-effective child survival public health measure which are more affordable and accessible to community in preventing diseases. Government of India has undertaken several initiatives to strengthen maternal and child health services in the country and child immunisation being an important part of child healthcare system in India. The National Immunization Programme has taken many initiatives since its inception as Expanded Programme on Immunization in 1978. In recent years, there has been introduction of various newer vaccines. Introduction of pneumococcal vaccine in selected states in year 2017 and plan to scale up in the entire country is the newest change in National Immunization Schedule. This review aims to identify various articles related to pneumococcal infection and vaccine highlighting the burden, serotypic distribution, available vaccines, evidence regarding vaccine safety, efficacy, acceptability and cost effectiveness, in order to provide sufficient understanding on the demand and need of this vaccine in India. Important factors underpinned by this article are though there is a need of vaccination due to severe form of pneumococcal infections and antibiotic resistance due to which many developed countries have included PCV in their regular immunisation programmes, however studies regarding effectiveness of pneumococcal vaccines in developing countries like India, data regarding the burden of pneumococcal infections are not available. Also there are limited studies investigating the bacterial and viral etiology of Community Acquired Pneumonia and lack of data to show change in the serotype prevalence overtime. This review highlights the need of more research to provide substantial clinical and epidemiological evidence for the introduction of pneumococcal vaccine. ………………………………………………………………………………………………………………………………..


Introduction
Vaccination is undoubtedly one of the most costeffective child survival public health measure. Eradication of small pox underpins immense potential of immunization as a public health measure. Also, vaccines are more affordable and accessible to community in preventing diseases in comparison to therapeutic interventions [1].

History of Immunisation programme in India:
The Government of India has undertaken several initiatives to strengthen maternal and child health services in the country. Child immunisation is an important part of child health care system in India. The National Immunization Programme has taken many initiatives However, India's target for immunisation consists of an annual cohort of 26 million infants of which 38 percent does not receive all due vaccines. Moreover, there is also a large inter-state variation in the coverage of Routine Immunisation [3,4]. Government of India has also implemented intensive campaigns to further boost the immunization coverage through Mission Indra Dhanush (2014) and Intensified Mission Indra Dhanush. In recent years, there has been introduction of Introduction of Pneumococcal vaccine 2017

Method and Results
An update review (Non-systematic review) was conducted to identify various articles related pneumococcal infection and Pneumococcal Vaccine.
Relevant articles were selected forth is review that were published in Pub Med between 1990 to 2017 highlighting the burden and serotypic distribution of pneumococcal disease, available vaccines, evidence regarding vaccine safety, efficacy, acceptability and cost effectiveness.
Additionally, information was also extracted from published fact sheets and guidelines available to provide sufficient understanding in this context.

Burden of Pneumococcal Diseases in children
Global: Pneumonia is the single largest infectious cause of death in children worldwide. Globally 6% of neonatal deaths, 23% of post-neonatal and 15% of under-five deaths are due to acute respiratory infections. In 2015, Pneumonia killed 0.9 million children under the age of 5 and most of its victims were less than two years [5].
Incidence of Community Acquired Pneumonia in children under 5 years of age is 0.27 episodes per child-year in African region, followed by 0.26 in South East Asian region, 0.23 in Eastern Mediterranean region, 0.11 in Western Pacific region, 0.08 in American region, and 0.03 in European region [6].

Review Article
Public Burden of pneumococcal pneumonia in children: Pneumonia can be caused by a number of infectious agents, including viruses, bacteria, or fungi [8]. The most common bacterial causes are streptococcus pneumonia followed by Haemophilus influenza. Respiratory syncytial virus is most common cause of viral pneumonia [8].
Streptococcus Pneumonia (Pneumococcus) causes both severe and non-severe diseases. It is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide. Otitis media, sinusitis and bronchitis are more common, but less serious manifestations of this infection [9]. In developing countries, deaths from pneumococcal disease are common in children under 5 years. Many countries lack national estimates of exact burden of diseases caused by pneumococcus. However, the disease rates and mortality are higher in developing than in industrialized settings, with the majority of deaths occurring in Africa and Asia [8].
India: In India 5% of neonatal deaths, 28% of post-neonatal and 15% of under-five deaths are due to acute respiratory infections [5]. The pneumonia working group of Child Health Epidemiology Reference Group (CHERG) had estimated in 2004, incidence of 0.37 episodes per child year for clinical pneumonia among children < 5 years in India [10]. As per CHERG, in 2010, pneumonia was responsible for 0.397 million deaths of total estimated 1.682 million under-5 deaths in India [11]. Jaiswal N et al in a systematic review showed that S. Pneumonia in India causes 10.58% of invasive diseases, 7.62% of severe pneumonia cases, and 11.21% of meningitis cases in children with suspected bacterial diseases aged 1 month to 12 years [12].
According to Yadav KK et al (systematic review), in India, annually, 0.35-0.37 million deaths in children occur under 5 years of age due to Community Acquired Pneumonia (CAP), which is around 13-16% of total annual mortality in this age group. Among the Indian. states, Uttar Pradesh has the maximum number of CAP cases and deaths (24% cases, 26% deaths) in children under 5 years of age followed by Bihar (16% cases, 22% deaths), Madhya Pradesh (9% cases, 12% deaths) and Rajasthan (8% cases, 11% deaths). The case fatality rate (CFR) due to CAP in children under 5 years of age ranged from 2.5% to 11.8%.S. pneumoniae was most common organism (30-50%); followed by H. influenzae type b (8.8%) and Staphylococcus aureus (7-23%) [6]. However, there is no nationally representative study of any Pneumococcal Disease incidence from the community to reflect actual burden of the disease. The incidence of invasive pneumococcal disease (IPD) in India is difficult to estimate due to the large population and geographic size and the absence of a national surveillance system for IPD.

Sero-type Distribution of pneumococcal pneumonia
Global: Pneumococcus is classified into a number of serotypes, based on the composition of its outer capsule. There are more than 90 known serotypes whose prevalence varies by age, geographic region, disease spectrum, disease severity and overtime. A wide variety of serotypes cause non-invasive diseases such as otitis media and sinusitis, serotypes1, 5, 6A,

Review Article
Public This study does not consider the whole country as major part of central India was not represented. In a systematic review by Jaiswal N et al, serotype 14 was found to be the most common serotype followed by 5, 1, 19F, and 6B [12]. As per Yadav KK et al, serotypes 1 and 5 were found to be most prevalent followed by 4, 6A and 6B, 7, 12, 14, 15, 19F, 23, and 45 [6]. Data regarding change in the serotype prevalence overtime are lacking.

Different types of Pneumococcal Vaccines [16]
Types and Composition: Pneumococcal vaccines are two types: Pneumococcal Polysaccharide vaccine (PPsV) and Pneumococcal conjugate vaccines (PCV). PPsV is purified free polysaccharide derived from surface capsule of bacterium which is poor antigenic. PCV is resulted after conjugation of the capsular polysaccharide to a protein carrier.

Vaccine cost and cost effectiveness:
The current cost of the PCV vaccine is Rs. 1600/dose for PCV 10 vaccine and Rs. 3200/dose for the PCV 13 [16]. No study has been so far conducted in India regarding the cost-effectiveness of pneumococcal vaccines. Few European studies have shown favourable costeffectiveness of the vaccine.
However in a systematic review which included ten European studies regarding cost effectiveness of the new pneumococcal vaccines conducted by van de Vooren K et al suggested that though the studies supported the economic utility of the vaccine but as the studies included in the systematic review were mostly based on weak sources of data and had limited information on vaccine effectiveness, epidemiological and economic data. It is also suggested that wing to the dynamic issue of serotype replacement, it should be monitored post-licensure and, as changes occur, vaccine effectiveness and cost-effectiveness analyses should be re-evaluated [19].

Preparedness of Health System:
As per NFHS-4 data, immunisation coverage is around 62% in 2015-16 [2]. This underpins the fact that more efforts should be given in identifying and overcoming the barriers that impedes immunisation along with improving operational efficiency. According to Madhavi Y et al, Rs.200 crores were spent every year for procurement of the 6 UIP vaccines but only half of over 26 million birth cohort per year were immunised.
There was at least two-fold enhancement of total cost of procurement by inclusion of hepatitis-Bin Universal Immunisation Programme. Estimated cost of including the pentavalent vaccine in the UIP (in place of DPT) as per the same study is around Rs. 1200 crores (Rs. 400 crores from the Indian Government and Rs. 800 crores from Global Alliance on Vaccine Initiative, GAVI, though for a limited period of time). Inclusion of more vaccines will lead to even more increase in the total Government procurement budget with additional costs of logistics, cold-chain, syringes, manpower related costs. Hence, the public health needs before introduction of any vaccine needs to be undisputedly established [20].
Vaccine Acceptability: There is paucity of primary data on demand, utilization, and the access to pneumococcal vaccination in India. In an exploratory study conducted by Zodpey et al, it was found that 67.7% of the paediatricians recommended pneumococcal vaccination to their clients. Majority (97.3%) of the paediatricians reported that the main reason for a patient not following the advice for pneumococcal vaccination was the price of PCV.
Majority (74.1%) of the paediatricians argued that PCV should be introduced in UIP to enhance equity in the access to PCV to ensure the access of PCV to impoverished population which is also at high risk of pneumonia. On the contrary, very few (17.7%) of them were against its introduction owing to questions related to the efficacy and effectiveness of PCV in an Indian setting due to absence of any supporting evidence by clinical trial in India [21]. Similar findings were reported by Kahn GD et al [22]. A national survey conducted among the private sector paediatricians registered with the IAP has also reported that 85.6% of paediatricians administer PCV vaccine selectively or routinely [23]. Moreover, Farooque H et al estimated state-specific PCV coverage for the year 2012 had found that the overall PCV coverage in the private sector was around0. 33% (minimum 0.07% for Assamand maximum of 2.38% for Delhi). Overall PCV coverage in other major cities were13.31% for Mumbai, 0.76% for Lucknow, 1.93% for Kolkata and 4.92% for Chennai. It opined to improve PCV coverage among population by both the demand side and the supply side to remove inequity in PCV access [24].
Need of Pneumococcal vaccine in UIP: Pneumonia can be controlled by simple measures of prevention , protection and treatment like :Vaccination, Safe drinking water, good sanitation, and frequent hand washing with soap, improvement in indoor air quality, exclusive breastfeeding for first 6 months, good nutrition and recognizing danger signs of pneumonia and prompt initiation f treatment [8].
Pneumococcal diseases are a common cause of morbidity and mortality worldwide, though rates of disease and death are higher in developing countries than in industrialized countries, with majority of deaths occurring in sub-Saharan Africa and Asia [9]. Hence pneumococcal vaccines can be an important public health tool to reduce the burden of pneumococcal diseases along with other interventions particularly in developing countries including India.
The current cost of the vaccine justifies its inclusion in the National Immunization Program. But, introduction of pneumococcal vaccine in NIS raises certain issues like public health priority, assessment of candidate vaccine in the country and programmatic issues. Additional factors like change in serotypes, efficacy, and cost effectiveness and challenges like probability of the non-vaccine serotypes replacing the vaccine types, change in pattern in antibiotic susceptibility in the nonvaccine serotypes and establishment of sentinel surveillance of pneumonia to observe the trends and to obtain a measure of effect of pneumococcal vaccine needs to be explored and considered [25].

Conclusion
Pneumococcal disease, including pneumococcal pneumonia and pneumococcal meningitis, can be treated with antibiotics, usually amoxicillin. However, in many countries strains of pneumococcus are becoming resistant to some of the commonly used antibiotics [8]. Pneumococcal infections which are resistant to these antibiotics require treatment using more expensive antibiotics which underpins the need of vaccination. Many countries have included PCV in the irregular immunisation programmes [26]. Also, studies

Review Article
Public Health Review: International Journal of Public health Research Available online at: www.medresearch.in 244 | P a g e conducted regarding effectiveness of pneumococcal vaccines in developed countries in regards to how promising results are. These trends should not be used as a justification for their inclusion in the Indian Immunisation Programme as most of the available data on Pneumococcal diseases are on meningitis and from hospital-based studies.
Data regarding the burden of milder pneumococcal illnesses, such as sinusitis and otitis media are not available. Also, there are limited studies investigating the bacterial and viral etiology of Community Acquired Pneumonia; hence, more research is needed in this context. Introduction of pneumococcal vaccine in India should be based on substantial clinical and epidemiological evidence. In India the burden of pneumococcal disease is the greatest among the underprivileged children.
However, the high cost of PCVs and the limited coverage of the currently available vaccine are impediments. However, a wide variation in prevalent serotypes demands prospective studies to formulate recommendations for specific pneumococcal vaccine introduction. Studies of short duration either over-or underestimate the problem. Absence of data to show change in the serotype prevalence overtime poses questions regarding introduction of pneumococcal vaccine in the immunization schedule.