Indian J Pediatr DOI 10.1007/s12098-017-2449-3

REVIEW ARTICLE

Pneumococcal Vaccines – How Many Serotypes are Enough? Aaradhana Singh 1 & A. K. Dutta 2

Received: 14 May 2017 / Accepted: 31 July 2017 # Dr. K C Chaudhuri Foundation 2017

Abstract Streptococcus pneumoniae causes meningitis, pneumonia, septicemia, arthritis, sinusitis and otitis media specially in children and over 65 y age groups. It contributes significantly to under-five mortality and morbidity worldwide as well as in India. Use of pneumococcal vaccine seems to be the most effective measure to decrease the disease burden and reduction of under-five mortality. Many countries have already included Pneumococcal Conjugate Vaccines (PCV) in their National Immunization Programmes (NIP). Government of India has announced recently to include PCV13 in NIP in a phased manner. Superiority of a vaccine over the other depends upon serotype coverage, vaccine efficacy, cost effectiveness and safety profile. These facts will be discussed for the vaccines available in India. Further research is warranted to know the disease burden and develop vaccines to have more serotype coverage. Keywords Invasive pneumococcal disease (IPD) . Pneumococcal conjugate vaccine (PCV) . National immunization programme (NIP)

Introduction Pneumococcal infections include serious diseases such as pneumonia, meningitis, septicemia and osteoarthritis as well * Aaradhana Singh [email protected]

1

Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, New Delhi, India

2

Department of Pediatrics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India

as milder diseases such as otitis media and sinusitis. The causative agent, Streptococcus pneumoniae, colonizes the nasopharynx and is transmitted by respiratory droplets. Streptococcus pneumoniae is among the most important etiological agents of bacterial pneumonia, meningitis and sepsis in children. Invasive pneumococcal disease (IPD) is associated with isolation of pneumococci from sterile body sites such as in meningitis and septic arthritis. Pneumonia is often caused by aspiration of pneumococci from the nasopharynx. When associated with bacteremia, pneumonia is classified as IPD. Children <2 y of age are affected the most. S. pneumoniae is responsible for 15–50% of all episodes of community acquired pneumonia, 30–50% of all cases of acute otitis media and a significant proportion of bacterial meningitis and bacteremia [1–3]. Pneumonia is by far the most common cause of pneumococcal death worldwide [4]. A recent United Nations Children’s Fund (UNICEF) publication estimated that 410,000 children under age five years die of pneumonia each year in India, and a recent data shows that an estimated 25% of all child deaths in India are due to pneumonia [5]. Case fatality rates for IPD are as high as 20% for septicemia and 50% for meningitis in developing countries. Long term neurologic sequelae are found in as high as 58% of cases of meningitis survivors. Pneumococcal disease is a serious global problem with an estimated 14.5 million episodes of invasive pneumococcal disease (IPD) and approximately 500,000 deaths each year in children under five years of age, almost all from lowand middle-income countries as per the reports of Centers for Disease Control and Prevention (CDC) [6]. Pneumococcal disease has such a high disease burden, mortality and morbidity that WHO in 2007 recommended to include Pneumococcal Conjugate Vaccines (PCV) in the National Immunization Program (NIP) of any country with under-five mortality rate (MR) of >50/1000 live births or absolute child deaths of >50,000 per year. With under-five MR

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of 72/1000 live births and nearly 2 million under-five deaths per year, India merits to include PCV in NIP with high priority. The Union Health Ministry has approved the introduction of pneumococcal vaccines in Himachal Pradesh along with four other states under the Universal Immunization Programme (UIP). The pneumonia vaccines will be introduced in a planned manner from 2017 in Himachal Pradesh, Bihar, Uttar Pradesh, Rajasthan, Haryana and Madhya Pradesh. India is not able to develop any indigenous vaccine against pneumonia but GAVI has promised to offer present PCV13 vaccine at a cost of 0.15–0.3 USD/dose for inclusion in the national immunization schedule.

Pneumococcal Serotypes S. pneumoniae is a Gram-positive encapsulated cocci. Currently, more than 90 immunologically distinct capsular serotypes have been described which possess distinct epidemiological properties [7]. Some serotypes are associated only with nasopharyngeal (NP) carriage and rarely cause invasive disease. Less than 20 serotypes cause >90% of IPD worldwide [8]. Table 1 shows the studies on prevalent pneumococcal strains in India and Asian countries.

Pneumococcal Vaccines Various pneumococcal vaccines have been developed which contain different serotypes as it is not possible to incorporate all serotypes in a single vaccine. Two broad categories of pneumococcal vaccines are: Pneumococcal Polysaccharide Vaccine (PPSV23) and Pneumococcal Conjugate Vaccine (PCV). 1. Pneumococcal Polysaccharide Vaccine (PPSV 23) – 23 valent polysaccharide vaccine is available since 2009 and contains 1,2,3,4,5,6B,7F,8,9 N,9 V,10A,11A,12F,14,15B,17F,18C,19A,19F,20,22F,23F, and 33F. PPSV 23, being a polysaccharide Table 1

vaccine is not used for routine immunization in children due to poor immunogenicity in children <2 y of age. So, it is used for special conditions and in elderly. 2. Pneumococcal Conjugate Vaccine – PCVs were developed primarily to address the problem of low immunogenicity of the polysaccharide vaccine in children below the age of two years who are at high risk for pneumococcal disease. Conjugation of the pneumococcal polysaccharide of varying number of serotypes has been done with CRM197 protein, protein D of non-capsulated Hib (Hemophilus i nfluenzae type b va ccine) , DT (Diphtheria, Tetanus vaccine) and TT (Tetanus toxoid vaccine) and finally Meningococcal Outer Member Protein (OMP). Three pneumococcal conjugate vaccines are: PCV7 (not available after introduction of PCV 13), PCV10, and PCV 13. PCV 7 contains polysaccharide antigen of serotypes 4, 6B, 9 V, 14, 18C, 19F and 23F linked to CRM197. Inadequate coverage of serotypes by PCV 7 has led to the formulation of PCV 10 that provides additional protection against 1, 5 and 7F, carrier being non-typeable Haemophilus influenza protein D. PCV 13 protects against 1, 5, 7F, 6A and 19A, in addition to serotypes in PCV 7 conjugated with CRM 197 diphtheria protein [13]. PCV 7 was originally recommended as an optional vaccine by the Indian Academy of Pediatrics (IAP) [14], but was removed from the market since 2010. PCV-10 and PCV-13 are now recommended for use as routine vaccines under the IAP schedule [15]. Table 2 shows serotypes covered by PCV 10 and PCV 13 and recommended IAP immunization schedule.

Safety Profile Favorable safety profile of PCV 7 is established [16, 17]. Several studies show safety profile of PCV10 and PCV13 similar to PCV 7 [18–25]. Main adverse events are: injection site reactions, rash, headache, fatigue, joint pain, fever and

Studies showing prevalent serotypes of S. pneumoniae

Studies

Regions

Serotypes

Serotype coverage by PCVs

Balaji et al. [9]

South India

14(19.5%), 19F (12.2%), 5(8.7%), 6A (8.7%), 6B (8, 7%)

PCV10–64% PCV13–74.6%

Shariff et al. [10]

Delhi

PCV10–54% PCV13–73%

ANSORP study [11] IBIS group, INCLEN [12]

11 Asian countries India

19 (26%), 6 (11%), 7 (10%), 1 (9%), 14 (7%), 9 (5%), 33 (4%), 17 (4%), 11 (2%), 3 (2%), 18 (1%), 23 (1%), 12 (1%), 32A (1%), 15B (1%), 22F (1%), 5 (1%), 29 (1%), non-vaccine type E (1%), F (1%), H (7%), 19 A (6%) 19F (23.5%), 23F (10%), 19A (8.2%), 14(7.3%), 6B (7.3%), 3(6.2%), 6A (4.2%) 6,1,19,14,4,5,45,12,7. Serotypes 1 and 5 account for 29% isolates

PCV Pneumococcal conjugate vaccine

PCV7–52.5%

Indian J Pediatr Table 2

Pneumococcal conjugate vaccine (PCV) schedule in children (IAP 2016)

Vaccine

Serotypes covered

Routine vaccination

Catch up vaccination

PCV 10 (synflorix)

4,6B,9V,14,18C,19F 23F (covered by PCV7) plus additional 3–1,5,7F

Primary vaccination −6,10,14 wk of age Booster at 12–15 mo of age

6–12 mo age

2 doses 4 wk apart and one booster

PCV 13 (Prevanar13)

Serotypes covered by PCV10 plus additional 3–3, 6A, 19A

Primary vaccination – 6,10,14 wk of age Booster at 12–15 mo of age

12 mo – 5 y 6–12 month

2 doses 8 wk apart 2 doses 4 wk apart and one booster

12–23 mo

2 doses 8 wk apart

24 mo – 5 y

Single dose

decreased appetite. Rare side-effects being bronchiolitis, pneumonia and gastroenteritis. Vaccine Efficacy Table 3 shows efficacy of the vaccine in pneumococcal diseases.

Pneumococcal Vaccine in High Risk Cases PCV13 and PPSV23 vaccines are used for high risk cases such as chronic heart disease, chronic lung disease, diabetes mellitus, cerebrospinal fluid leak, cochlear implant, functional/anatomic asplenia like sickle cell disease, and immunocompromising conditions such as HIV infection, treatment with immunosuppressive drugs or radiation therapy and congenital immunodeficiency.

Cost-effectiveness Cost-effectiveness of PCV vaccine depends upon the disease burden, prevalent strains, vaccine cost and number of doses used. A study conducted in Denmark and Sweden compared cost-effectiveness of PCV10 vs. PCV 13 and found PCV13 to be more cost-effective [35]. PCV 13 was found to be more cost effective in a study conducted in Canada also [36] Whereas in Argentina, both were found to be equally costeffective [37]. WHO Schedule WHO has recommended two types of schedules for inclusion of PCV in NIP of low- and medium-income countries. Table 4 show comparison between the two schedules. In choosing between the 3p + 0 (3 Primary + 0 Booster) and 2p + 1 (2 Primary + 1 Booster) schedules, countries should consider locally relevant factors including the age distribution of pneumococcal disease, the likely vaccine coverage, and the timeliness of the vaccine doses [38].

PCV 10 vs. PCV 13 There are no comparative studies in India regarding efficacy, safety profile and cost-effectiveness of PCV10 and PCV13. Serotype coverage is the only parameter where we have comparative studies between the two. As clearly evident from Tables 1 and 2, most of the serotypes prevalent in India are being covered by PCV13. So PCV 13 is to be included for routine immunization in India in a phased manner. Here it is essential to mention serotype 19A. Two studies from India show emergence of multidrug resistant (MDR) 19A strains: One is ANSORP (Asian Network for surveillance of resistant pathogen) study which showed that 8.2% of isolates were 19A serotype, out of which 86.0% and 79.8% were erythromycin resistant and MDR respectively [11]. Another one is a study conducted in Delhi by Shariff M et al., 2013 where 6% of isolates were of 19A serotype [10]. PCV13 has immunogenicity similar to PCV7 in response to the 7 common serotypes, and has generally higher immunogenicity in response to the 6 additional serotypes. PCV13

Table 3 Vaccine efficacy of PCV Disease

Pooled vaccine efficacy

Invasive pneumococcal disease (IPD) [26]

For vaccine serotypes – 80% (95% CI 58% to 90%, P < 0.0001)

Radiologically defined pneumonia [27, 28] Clinically defined pneumonia [29] Otitis media [30–32]

For all serotypes – 58% (95% CI 29% to 75%, P = 0.001) 27% (95% CI 15% to 36%, P < 0.0001) 6% (2% to 9%, P 0.0006) Recurrent otitis media – 10–50%

Nasopharyngeal carriage [33, 34]

Severe otitis media – 39–66% 16.6% – 18.3%

Indian J Pediatr Table 4

Comparison of 3p + 0 and 2p +1 schedules of PCV

Dosing schedule

<1y

3p + 0 schedule

2p + 1 schedule

Primary doses

3 doses at 6,10,14 wk or 2, 4, 6 mo alongwith pentavac and rotavirus vaccines

< 6 mo

2 doses. As early as 6 wk and 8 wk gap between 2 doses

>6 mo

4 wk gap between two doses

Booster

No booster 2 doses 8 wk apart

1 booster at 15 mo of age with measles and vit A 2 doses 8 wk apart

>2 y with high risk Immunogenicity after primary doses

2 doses 8 wk apart More

2 doses 8 wk apart Less

Immunogenicity after full doses

Less

More

1–2 y

may provide added protection against pneumococcal disease caused by the additional 6 serotypes and does not interfere with immune responses to whole-cell pertussis and oral poliovirus vaccines. PCV13 has an acceptable safety profile in both infants and toddlers, comparable with that of PCV7 [24].

Barriers in Introduction of PCV in India There are many issues to confront with before introducing PCVs in NIP of the country. These are: 1. The paucity of data on disease burden and serotype prevalence – Before introducing any vaccine in National Immunization Programme (NIP), it is desirable to have data on disease and prevalent serotypes which is representative of whole country. But in India we lack comprehensive data with very few single site and multisite studies available so far. The main reason of such paucity of data is complex procedures required to isolate and serotype the organism. Table 1 shows few studies conducted in Asian countries and India. Pre antibiotic use limits the invasive pneumococcal incidence detection around 39 to 60% [39]. Serotype distribution remains almost similar in both culture positive and culture negative IPD. Effort by the Asian Strategic Alliance for Pneumococcal Disease Prevention (ASAP) Working Group to collate data on the disease burden due to invasive pneumococcal disease (IPD) in participating Asian countries and territories namely, Hong Kong, India, Indonesia, Korea, Macau, Malaysia, Pakistan, the Philippines, Singapore, Sri Lanka, Taiwan and Thailand confirms that data regarding the incidence of IPD in Asia are grossly lacking and reinforces the need for urgent and more substantial studies [40]. 2. Replacement of vaccine types by non-vaccine types – PCV 7 has led to dramatic decline in disease burden in countries where it was introduced. In United States alone, IPD in children <5 y age group decreased by 94% [41].

After introduction of PCV 7, surveillance studies from the US showed a decrease in cases of IPD due to vaccine serotypes (VT) and an increase in cases due to nonv a c c i n e s e r o t y p e s ( N V T ) , t h e Br e p l a c e m e n t phenomenon^ [42]. Serotype replacement among adult pneumococcal pneumonia after the vaccination of children with PCV7 was evident in the Japanese population [43]. Serotype replacement of VTs by NVTs may dilute the effect of PCV after some time. Drug resistant NVTs may pose serious problem and may even increase disease mortality. In view of variation in the proportion of isolates serotyped before and after vaccine introduction, changes in blood culture practice, and outbreaks of pneumococcal disease, there is a need for caution in interpreting pneumococcal disease surveillance data. 3. Antibiotic susceptibility pattern change in the nonvaccine serotypes – Polymerase chain reaction (PCR) in culture-negative pneumococcal empyema due to prior antibiotic treatment has clearly established the role of nonvaccine types in the etiology [44]. 4. Limitations of the conjugate vaccines to protect against non-vaccine serotypes – This needs to be overcome by exploring other virulence factors that may have potential advantages. Specific capsular serotypes are responsible for pneumococcal disease and influence the outcome. One of the major limitations of the current polysaccharide vaccine is their inability to protect against non-vaccine serotype infections. This warrants the development of alternatives that may protect against pneumococcal disease across all serotypes. Martens et al. [45] suggested that the virulence of pneumococcal serotypes should be considered in the design of novel vaccines. A study by Gopi et al. showed significant genetic diversity within S. pneumoniae isolates thereby indicating the need of continued molecular surveillance of S. pneumoniae to be necessary to monitor pneumococcal population dynamics and capsular switching events at the genetic level prior to and after PCV introduction in NIP [46].

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Hence pneumococcal disease, being a big contributor to under-five mortality in India needs to be given special attention as public health problem. The most effective way to reduce pneumococcal disease burden is by inclusion of pneumococcal vaccine in National Immunization Programme. Government of India has taken a step forward and has announced introduction of pneumococcal conjugate vaccine in NIP in a phased manner. Since PCV13 covers most of the serotypes prevalent in India especially MDR 19A serotype, it seems to be the vaccine of choice in India. There is an urgent need to develop an effective surveillance system after introduction of PCV13 in NIP to keep a track on vaccine efficacy, adverse events following immunization (AEFI), disease burden, serotype replacement and antibiotic susceptibility pattern of serotypes.

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Compliance with Ethical Standards 17. Conflict of Interest None. Source of Funding None.

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