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 ~ Introduction
 ~  Epidemiology of ...
 ~  Monitoring of An...
 ~  Pneumococcal vac...
 ~  References

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REVIEW ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 4  |  Page : 465-474
 

Pneumococcal vaccines


1 The CHILDS Trust Medical Research Foundation, Chennai, Tamil Nadu, India
2 Department of Clinical Microbiology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India

Date of Web Publication18-Mar-2019

Correspondence Address:
Dr. Anand Manoharan
The CHILDS Trust Medical Research Foundation, 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_18_442

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 ~ Abstract 

Streptococcus pneumoniae continues to take a heavy toll on childhood mortality and morbidity across the developing world. An estimated 10.6 million invasive pneumococcal diseases (IPDs) occur every year, with nearly 1 million deaths in children under 5 years of age. Introduction of vaccines in the childhood immunisation programme in developed world has brought down the incidence of the disease considerably. However, childhood immunocompromising illnesses including HIV have increased the risk of IPD several folds. There is also a growing concern on the increasing antibiotic resistance among these invasive strains to penicillin, other beta-lactams and macrolides, making treatment difficult and expensive. It is estimated that about 62% of IPD worldwide is caused by the 10 most common serotypes. Although the ranking of individual pneumococcal serotypes causing serious disease varies among nations, the 7–13 serotypes included in pneumococcal conjugate vaccines (PCVs) may prevent 50%–80% of all paediatric pneumococcal diseases globally. The World Health Organization has recommended the use of PCV-10/13 in the national immunisation programmes (NIPs) of developing countries. Four doses of PCV-13 have been recommended by the US Association of Pediatrics and Centers for Disease Control and Prevention, at intervals of each 2 months for the first 6 months and by the 12th to 15th months after birth. This is expected to reduce the morbidity and mortality associated with IPD and simultaneously decrease colonisation with circulating antibiotic-resistant strains in immunized communities. Nevertheless, continued surveillance of antimicrobial resistance in non-vaccine serotypes is necessary to prevent the resurgence of resistance. Other virulence factors which are not serotype specific also need to be studied to overcome the drawbacks of serotype-specific pneumococcal vaccines. PCV-13 was launched during May 2017 under the NIP of five Indian states with the highest pneumococcal diseases in the country and is expected to be rolled out in the other parts of the country in the coming days.


Keywords: Antibiotic-resistant serotypes, invasive pneumococcal disease, pneumococcal vaccines


How to cite this article:
Manoharan A, Jayaraman R. Pneumococcal vaccines. Indian J Med Microbiol 2018;36:465-74

How to cite this URL:
Manoharan A, Jayaraman R. Pneumococcal vaccines. Indian J Med Microbiol [serial online] 2018 [cited 2019 Nov 16];36:465-74. Available from: http://www.ijmm.org/text.asp?2018/36/4/465/254402



 ~ Introduction Top


Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia, meningitis, bacteraemia and acute otitis media (AOM) in children below 5 years.[1] Invasive pneumococcal disease (IPD), referred to as isolation of pneumococci from normally sterile body sites, most frequently affects children <2 years old, immunocompromised children with sickle cell disease, or children with HIV/AIDS. The incidence of IPD in young children is expected to rise as an increasing number of African and Asian children are born with a perinatally acquired HIV infection.[1],[2] With the introduction of Haemophilus influenzae type b (Hib) vaccines, reduction of Hib infections and takeover of IPD have been observed in many countries including India.[3],[4] Furthermore, IPD in the developing world is several times higher than that in industrialized countries due to socioeconomic differences and genetic factors. Development of penicillin resistance by pneumococci in several countries necessitates a change to more expensive antibiotics, adding to the burden of healthcare costs in developing countries. More than 90 serotypes of pneumococcus have been identified, but only approximately 23 serotypes produce the majority of IPD. About 62% of invasive disease worldwide is caused by 10 most common serotypes.[5],[6] In India, there is a paucity of IPD disease burden data largely due to the challenges for the isolation and accurate identification of pneumococci from clinical specimens.[7] In addition, convention serotyping (antisera based) is expensive; however, simple and efficient methods such as polymerase chain reaction for serotyping pneumococci are available in India, but their application in Indian laboratories is still limited.[8]


 ~ Epidemiology of Streptococcus Pneumoniae Infections in Children Top


Global scenario

Globally, in 2000, an estimate found about 14.5 million episodes of serious pneumococcal disease (uncertainty range: 11.1–18.0 million) with 826,000 deaths (582,000–926,000) in children aged 1–59 months, of which 91,000 (63,000–102,000) occurred among HIV-positive and 735,000 (519,000–825,000) among HIV-negative cases. Of the deaths in HIV-negative children, over 61% (449,000 {316,000–501,000]) occurred in ten African and Asian countries. Overall, pneumococcuscauses around 11% (8%–12%) of all deaths in children aged 1–59 months (excluding pneumococcal deaths in HIV-positive children) in the world, with India ranking number one among the countries with highest pneumococcal deaths.[9],[10] This mandates prevention and treatment of pneumococcal disease, especially in regions of the world with the greatest burden in order to achieve Millennium Development Goal 4.

To avoid differences in the data in surveillance studies of IPD in Africa and Asia, investigators of Pneumococcal Vaccines Accelerated Development and Introduction Plan-sponsored projects have developed standard case definitions and data reporting method. Their analysis showed CSF had a higher proportion pneumococcus positivity (1.2%-19.4%) than blood (0.1%-1.4%) among all countries (range, 1.3-38-fold greater) surveyed. Furthermore, IPD detection varied by syndrome (meningitis, 1.4%–10.8%; pneumonia, 0.2%–1.3%; other, 0.2%–1.2%) and illness severity (nonsevere pneumonia, 0%–2.7% and severe pneumonia, 0.2%–1.2%), although these variations were not consistent for all sites. Antigen testing and polymerase chain reaction increased the proportion of pneumococcal detection in CSF specimens by 1.3–5.5 folds, compared with culture alone.[11]

The Asian Strategic Alliance for Pneumococcal Disease Prevention (ASAP) showed that disease incidence and mortality rates of IPD vary across the region.[12] The World Health Organization (WHO) estimated that IPD incidence among children under five was 3,627 and 2,991 in Southeast Asia per 100,000. In Europe, in 2000, it was only 504/100,000, while it was much higher in the US.[13],[14] In Utah, US (1996–2010), the median age of children with IPD increased from 19 to 27 months after vaccination (P = 0.02). Gambia, West Africa, had 554 and 240/100,000 IPD in children younger than 1 and 5 years, respectively (mean age: 15 months), with pneumonia higher than meningitis, but mortality was 1% and 55%, respectively.[15] Arabian Peninsula and Egypt (1990–2007) had an IPD incidence of 3.4–53.5/100,000. Bacteraemia was seen in 61%–100% (children <2 years) of the total IPD. Pneumococcal meningitis cases ranged from 3% to 25% in children <2 years and 7%–30% in those ≤5 years. Case fatality and morbidity rates for pneumococcal meningitis were 0%–22% and 10%–62%, respectively in these regions.[16] In a population-based surveillance of 12,000 children below 5 years in rural Bangladesh, the overall IPD incidence was 86 cases/100,000 child-years, most commonly during infancy. Fifty percent of the isolates were obtained from nonhospitalised patients who had upper respiratory tract infection and fever.[17]

In central Australia, serotypes 14, 6B, 9V, 4, 18C and 19F accounted for 67% of paediatric isolates.[18] A multinational study (nine data sets) on AOM (1994––2000) identified that 60%–70% of the pneumococcal isolates among 6 to 59 month old children belonged to pneumococcal conjugate vaccine (PCV-7) serotypes. Serotypes 3, 1 and 5 included in PCV-13 were most common in children <6 months old.[19] The ASAP reported that PCV-7 covered 56.9% of disease serotypes in India and 89.8% in Hong Kong.[12] In Arabian Peninsula and Egypt, serotypes covered by the PCV-7 ranged from 49% to 83% (<2 years) and from 61% to 69% (≤5 years), respectively. Pneumococcal meningitis cases were most commonly caused by serotypes 14, 23F, 6B, 19F and 6A (≤5 years).[16] Out of the 23 isolates of pneumococcus, from IPD in Colombo, Sri Lanka (January 2005 to March 2007), 19F, 14, 23F and 6B were most common, 60% of which were covered by PCV-7.[20] AOM (31%) and IPD (42%) were caused by 11 major non-PCV-7 serotypes (1, 3, 5, 6A, 7F, 12F, 15B/C, 19A, 21, 33F and 35B) among Jewish and Bedouin children in <5 years old age group in Southern Israel (1999–2008), preceding PCV-7 implementation.[21] Non-PCV-7 serotypes 7F, 19A, 22F and 3 were predominant in the post vaccine period. During 2005–2010, 67% of the cases of IPD were caused by serotypes contained in PCV-13.[22] In Nigeria, 23 IPD cases were identified in three urban hospitals, which were caused by serotypes 5, 19F and 4 included in PCV-13.[23] In a surveillance of the South Asian Pneumococcal Alliance network done at a children's hospital, Kathmandu, Nepal, IPD was most commonly caused by serotypes 1, 5, 2 and 7F, followed by 12A, 19B and 23F, majority of which were included in PCV-13.[24] Similarly, PCV-13 vaccine serotypes 1, 5, 14, 18C and 19A were commonly reported from Bangladesh.[17]

Penicillin resistance ranges from 1% in the Philippines to 55.4% in South Korea.[12] Penicillin resistance among invasive isolates from Arabian Peninsula and Egypt ranged from 0% to 78% respectively.[16] Of all the invasive isolates from Nepal, 3.8% were resistant to penicillin and 68% were resistant to trimethoprim-sulfamethoxazole.[24] In a study from Colombo, Sri Lanka, more than 90% of the 23 isolates were penicillin resistant, and the rate of resistance to third-generation cephalosporins was also high.[20] Ten of the 26 pneumococcal isolates in a study from Bangladesh were completely resistant to trimethoprim-sulfamethoxazole, and another 10 isolates had intermediate resistance.[17]

Indian scenario

The report 'Pneumonia: The Forgotten Killer of Children' published by the WHO/UNICEF in 2006 states that more than half of all pneumonia cases worldwide occur in the Asian-Pacific region. Of the 133 million childhood pneumonia cases around the world in 2005, India accounted for 44 million and China accounted for 18 million cases. Five of the top 10 countries with the highest burden of PD are in Asia – Bangladesh, China, India, Indonesia and Pakistan, with India accounting for almost 25% of the world's pneumonia child deaths.

In a study from a tertiary care hospital in Vellore, Tamil Nadu, involving children under 5 years with IPD, 42 isolates were obtained, with serotypes 5, 6 and 7 accounting for 79% of cases, though 3, 4, 10, 11, 12, 13, 19 and 20 were less common.[25] Nasopharyngeal (NP) colonisation studies on pneumococcus had determined the most common serotypes from infants and children below 3 years in two tertiary care hospitals in South India. One study found the median age of acquisition of pneumococci in infants to be 11 weeks, with a median age of duration of 1–3 months.[26] Serotype 1 was most common followed by 6, 19, 14, 15, 2, 3 and 4 in children between 3 months and 3 years of age, and the carriage rate was 6.5%. A prevalence rate of 24.3% was noted in healthy school children between 5 and 10 years of age in another study from Puducherry.[27] In a study from Madurai, Coles et al. have reported the most prevalent serogroups/types during the first 6 months of life to be 6, 9, 10, 11, 14, 15, 19, 23 and 33, which accounted for 76.7% of all serotyped isolates.[28] A North Indian study reported pneumococcuscarriage rate to be 6.5%. The isolates belonged to serogroup/types 1, 6, 14 and 19, of which serogroup 19 was the most common in children between 3 months and 3 years of age.[29]

Two major hospital based sentinel studies have estimated the incidence of IPD among Indian children <5 years old. The first study was done in six tertiary care hospitals in India by the Invasive Bacterial Infection Surveillance (IBIS) group in which IPD was detected in 71 children <2 years, 32 children between 2 and 5 years and 211 children >5 years. Overall 70% of the isolates belonged to serogroup/types 1, 6, 19, 14, 4, 16 and 18, with serogroup/types 6, 1, 19, 4, 4, 5, 45, 12 and 7 being found commonly in children under 5 years. Serotypes 1 and 5 accounted for 29% of IPD cases.[30]

The second major study was done by the Alliance for Surveillance of Invasive Pneumococci (ASIP). This prospective hospital and retrospective laboratory-based surveillance study, enrolled children aged younger than five years with suspected or proven IPD from 18 hospitals or institutional centres. This study also retrospectively included laboratory-confirmed pneumococcal isolates from 10 sentinel laboratories, together representing 11 states in India.

Between Jan 1, 2011, and June 30, 2015, the study enrolled 4377 patients. Among 361 (8%) patients with culture proven pneumococcal disease, all clinical data were known for 226 (63%); among these patients, 132 (58%) presented with pneumonia, 78 (35%) presented with meningitis, and 16 (7%) had other clinical conditions. 131 (3%) died overall and 29 (8%) patients with IPD died. Serotypes 14 (52 [14%] of 361), 1 (49 [14%]), 5 (37 [10%]), and 19F (33 [9%]) were the most common. Penicillin non-susceptibility occurred in isolates from 29 (8%) patients, co-trimoxazole resistance occurred in 239 (66%), erythromycin resistance occurred in 132 (37%), and chloramphenicol resistance occurred in 33 (9%). In this study, multidrug resistance (MDR) was found in 33 (9%) of 361 patients.[31]

Another report from a tertiary care hospital in Puducherry noted that 59.3% of the isolates from IPD belonged to serogroup/types 1 (most common), 6, 19, 5, 23 and 7. Nineteen isolates (12.6%) were non-vaccine types.[32] In a study from Dibrugarh in Assam in North East India, serogroups/types 33, 8, 1, 19, 6 and 23 accounted for 62.5% of isolates from a cluster of rural children between 0 and 14 years of age.[33]

A study from South India looking at the incidence of IPD in all age groups found serotype 1 (the most common) followed by serotypes 5, 19F, 6B and 14 as the predominant serotypes.[34] A 7-year laboratory-based IPD surveillance in children from Vellore identified 114 IPD isolates and serotypes 14, 19F, 5, 6A and 6B as the predominant serotypes, and 25.4% of isolates were non-PCV-13 types.[35]


 ~ Monitoring of Antimicrobial Resistance and Mapping Serotypes of Streptococcus Pneumoniae : Impact on Pneumococcal Vaccines Top


Antibiotic resistance among different serotypes of pneumococcus has been a growing global problem. Infection with drug-resistant pneumococcal strains has resulted in treatment failures among children with otitis media and meningitis, largely because of the difficulty in achieving adequate antibacterial concentrations in the middle ear and CSF.[36] The spread of antibiotic resistance has further stirred the development of vaccines that might be able to prevent pneumococcal disease in infants and children below 5 years.

The Alexander project studied the global prevalence of penicillin resistance among pneumococci, and the rates of resistance estimated as of 1997 were USA (18.6%), Mexico (36.5%), South Africa (4.5%), Western and Eastern Europe (13.4% and 9.8%), Saudi Arabia (6.5%) and Hong Kong (55.5%).[37] This study also found that macrolide resistance was a growing problem as of 1997 in several countries, more than penicillin resistance. In Uruguay resistance to penicillin, generally combined with trimethoprim-sulfamethoxazole, fluctuated annually, not surpassing 10%.[38]

The overall mean annual incidence of IPD in European children aged <2 years was 44.4/100,000, with a case fatality rate of 3.5% (1990–2008). The resistant rates for penicillin, erythromycin and third-generation cephalosporins were 23%, 41% and 9%, respectively.[39] In the Metropolitan Toronto and Peel Region (population, 3.1 million) of Canada, the prevalence of reduced antibiotic susceptibility among NP isolates and invasive isolates, respectively, was as follows: penicillin (16% vs. 11%); erythromycin (12% vs. 7%) and MDR (16% vs. 12%). Trimethoprim/sulfamethoxazole resistance was more common in NP carriage isolates than that in invasive isolates (38% vs. 23%, P = 0.02). Antibiotic-resistant isolates were predominantly serogroups 6, 19 and 23.[40]

In a northeastern Romanian orphanage, NP colonisation with pneumococcus and antibiotic resistance were studied (May 1996) among 162 HIV-negative (age range, 1–38 months) and 40 HIV-infected cases (age range, 39–106 months). Pneumococcus was isolated from 30% HIV-infected and 50% HIV-negative children. Ninety-eight percent of isolates were of 6A, 6B, 19A and 23F. Ninety-nine percent of these isolates were resistant to penicillin, and 74% were highly resistant to penicillin. Eighty-nine of 91 isolates were susceptible to ceftriaxone; 99%, 87%, 87%, 48% and 21% of the isolates were resistant to trimethoprim-sulfamethoxazole, erythromycin, clindamycin, tetracycline and chloramphenicol, respectively. Eighty-two percent isolates were MDR; 37 of 92 (40%) isolates were resistant to five or more antibiotic classes, and 16 of these 37 (43%) belonged to serotype 19A. All serotype 19A isolates were highly resistant to penicillin.[41]

Several prospective surveillance studies have been reported from Asian countries including India. In the latter half of the 1990s, penicillin non-susceptible pneumococcus strains were isolated from IPD in 11 Asian countries (September 1996 to June 1997): Korea (79.7%), Japan (65.3%), Vietnam (60.8%), Thailand (57.9%), Sri Lanka (41.2%), Taiwan (38.7%), Singapore (23.1%), Indonesia (21.0%), China (9.8%), Malaysia (9.0%) and India (3.8%). Serotypes 23F and 19F were the most common.[42] The most common serogroups were 6 (21.5%), 23 (16.5%) and 19 (15.7%).[43] Erythromycin resistance was 59.3% in IPD seen in ten Asian countries except Thailand and India between 1998 and 2001.[44]

An international surveillance done in 11 Asian countries during 2000–2001 showed pneumococci with the highest prevalence of penicillin resistance in Vietnam (71.4%), Korea (54.8%), Hong Kong (43.2%) and Taiwan (38.6%). Erythromycin resistance was as follows: Vietnam (92.1%), Taiwan (86%), Korea (80.6%), Hong Kong (76.8%) and China (73.9%). Ciprofloxacin resistance was as follows: Hong Kong (11.8%), Sri Lanka (9.5%), the Philippines (9.1%) and Korea (6.5%). As shown by multilocus sequence typing (MLST) studies, spread of 19F (Taiwan) and 23F (Spain) clones could be one of the major reasons for the rapid increases in antimicrobial resistance among pneumococcalisolates in Asia.[45]

The Asian Network for Surveillance of Resistant Pathogens studied (during 2008–2009) IPD cases at sixty hospitals in 11 Asian countries: the prevalence rate of penicillin non-susceptible pneumococci was 4.6% and penicillin resistance was extremely rare (0.7%). Overall, resistance to erythromycin was 72.7%, the corresponding resistance in various countries is as follows: China (96.4%), Taiwan (84.9%) and Vietnam (80.7%). MDR was found in 59.3% of isolates from Asian countries. Major serotypes were 19F (23.5%), 23F (10.0%), 19A (8.2%), 14 (7.3%) and 6B (7.3%). Overall, 52.5% of isolates showed PCV-7 serotypes, ranging from 16.1% in the Philippines to 75.1% in Vietnam. Serotypes 19A (8.2%), 3 (6.2%) and 6A (4.2%) were the most prominent non-PCV-7 serotypes in the Asian region. Among isolates with serotype 19A, 86.0% and 79.8% showed erythromycin resistance and MDR, respectively. After the introduction of PCV-7 in Asian countries, there is a high prevalence of macrolide resistance and MDR and distinctive increases in serotype 19A.[46]

Sixty pneumococcus isolates were obtained in children (2–59 months) with IPD, in a tertiary care hospital in Kathmandu, Nepal. Twenty-four of them (52.17%) were resistant to co-trimoxazole, and 3 (6.5%) were intermediately resistant to penicillin. One (2.17%) isolate was erythromycin and chloramphenicol resistant, and only one (2.17%) isolate was intermediately resistant to cefotaxime. The most common serotypes were 1 (27.65%) followed by 5 (19.14%), 4 (8.5%), 39, 23F, 7F, 19B, 12A, 14, 18F, 6B, 32, 16, 19F and 25F.[47]

The studies from a network of seven hospitals in Bangladesh (May 2004–2007) reported 139 pneumococcalisolates from IPD. Complete resistance against penicillin, chloramphenicol and co-trimoxazole was found in 0%, 6% and 32% of isolates, respectively. The predominant serotypes were 2 (17%), 1 (12%), 14 (7%), 5 (6%), 7F (6%), 45 (7%) and 12A (4%). Serotypes differed between meningitis cases and non-meningitis cases, especially for serotype 2. Overall, PCV-7, 10, and 13 would cover 20% (95% confidence interval [CI], 13%–27%), 43% (95% CI, 35%–51%) and 50% (95% CI, 42%–58%) of these cases of IPD respectively, with higher coverage of non-meningitis cases, compared with meningitis cases (7-valent coverage, 23% vs. 18%; 10-valent coverage, 55% vs. 38% and 13-valent coverage, 66% vs. 42%).[48]

In India, immunisation clinic- and community-based studies showed difference in resistance among invasive versus non-invasive pneumococcal infections in children under the age of five. In the first study, the percentage of co-trimoxazole resistance was only 5.4%, as compared to 64% in the community study.[26],[49] A study from Puducherry noted 11 (7.3%) isolates to be intermediately resistant to penicillin and 64 (41%) to be resistant to one or more antibiotics (trimethoprim/sulfamethoxazole, tetracycline and chloramphenicol). Resistance was distributed equally among the predominant serotypes.[32] In the surveillance study by the IBIS group, intermediate resistance to penicillin was noted in only 1.3% isolates, while resistance to trimethoprim/sulfamethoxazole and chloramphenicol was seen in 56% and 17% of isolates, respectively.[30] A study from Madurai showed that the prevalence of strains that were not susceptible to penicillin, co-trimoxazole and erythromycin was 34%, 81.1% and 37.2%, respectively. More than 87% of the isolates screened were non-susceptible to one or more antibiotic. Serogroups/types that were most frequently non-susceptible to one or more antibiotics were 6, 9, 14, 19 and 23.[50]

In a surveillance study from India since 1993, 5% of intermediate resistance to penicillin was recorded, with no MDR. Increasing minimum inhibitory concentration levels for erythromycin and cefotaxime were found among strains with intermediate resistance to penicillin, although they were still within the susceptible range.[51] Thereafter, the proportion of penicillin intermediate resistance to pneumococcus has increased steadily with 3.8% and 7.8% in 1996–1997 and 2000–2001, respectively, among the clinical pneumococcal isolates.[52] Among NP isolates of school children studied at seven centres in India (January–December 2004), sensitivity to trimethoprim/sulfamethoxazole varied, with as low as 6% in Mumbai, 29% in Chennai and Vellore and 100% in Delhi and Lucknow.[53] In a recent study from India by the ASIP network, penicillin and cefotaxime resistance was observed to be 7% and 4%, respectively. Resistance to co-trimoxazole and erythromycin was 70% and 33%, respectively.[31] A study from Vellore that included 830 IPD isolates from all age groups found 43.7% and 14.9% non-susceptibility to penicillin and cefotaxime, respectively, in pneumococcal meningeal isolates.[54] However, the penicillin non-susceptibility in pneumococcal non-meningeal isolates was only <1% in Indian settings. The difference within the percentage of non-susceptibility in meningeal and non-meningeal isolates could possibly be derived from the different susceptibility breakpoints for different clinical syndromes, as explained by Veeraraghavan et al.[55] Studies from elsewhere highlight the importance of resistance clones independent of serotypes in the emergence and worldwide spread of antibiotic resistance in pneumococcal isolates. This was evident with results from a study by Gopi et al. which demonstrated the influence of global Pneumococcal Molecular Epidemiology Network clones in Indian subcontinent.[56] This necessitates molecular techniques to be incorporated in surveillance studies to track the spread of resistant clones in India and elsewhere. High disease burden and mortality in children compounded with the emergence of MDR pneumococcus necessitates prioritisation of pneumococcal vaccination.


 ~ Pneumococcal vaccines Top


Evolution of pneumococcal vaccines

Although the first pneumococcal vaccine trials began in 1911, a vaccine (capsular polysaccharide [PS based]) was licensed only in 1977 in the US that included 14 serotypes. In 1983, the 23-valent pneumococcal PS vaccine (PPSV-23) was licensed and replaced the 14-valent vaccine. It was recommended for all patients aged 65 years or older and for children more than two years. Because this vaccine elicits a T-cell-independent response, it is less immunogenic in children less than 2 years of age who are more prone to IPD, thus necessitating the development of PCVs. These vaccines elicit a T-cell-dependent response, making them effective in children less than two year age group. In Children PPSV-23 vaccine is currently recommended only for high-risk children above two years following a PCV-10/13 dose.

Until April 2005, more than 20 vaccines have entered the preclinical phase through multinational emerging suppliers. More than five of the multivalent conjugate vaccines (7, 9, 10, 11 and 13 valent) have reached the clinical trial Phase III. The PCV-7 was licensed in the US in 2000, using capsular PS from selected seven serotypes conjugated to a protein carrier. It induced both systemic and mucosal immune responses to prevent NP colonisation by pneumococci.[57] The 9-valent and 11 valent vaccines have been discontinued by Phase-III clinical trial and the PCV-7 10 years after its licensing. The PCV-10 was launched in the US and Europe in 2008. In February 2010, the PCV-13 was licensed by the Food and Drug Administration / recommended by the Advisory Committee on Immunization Practices in the US covering 13 serotypes including those in PCV-7 and six additional serotypes. The additional serotype coverage is the result of epidemiologic changes due to serotype replacement post introduction of PCV-7 and including serotypes predominant from the developing world thus, allows broader prevention of IPD. By 2006–2007, only 2% of IPD cases in children younger than 5 years were caused by PCV-7 types, but the six additional serotypes included in the new PCV-13 vaccine caused 68% of IPD cases in this age group, mandating their inclusion in this second-generation vaccine.[58]

Thus, PCV-10/13 succeed PCV-7 use in the routine childhood immunisation schedule since 2010 and the American Association of Pediatrics recommends PCV-10/13 to be included in the universal immunisation of children <2 years old.

There seems to be differences of the benefits of pneumococcal vaccines between countries. Serotype distribution, and their coverage by the PCVs, varies among geographical areas. Moreover, a substantial serotype replacement effect after the PCV introduction is observed in some areas but not in others. For these reasons, experience from one geographical area, for example from the USA, cannot be directly applied to other countries. Strict epidemiological surveillance on PD in the pre and post PCV era is inevitable in all countries that start universal pneumococcal vaccinations as well as in countries where the vaccines are made available for the general public, to access the vaccine impact and to formulate future preventive strategies.

Available vaccines for pneumococcal infections

The currently available pneumococcal vaccines include the following two formulations:

  1. PS vaccines: Made with purified capsular PS antigens


    • PPSV-23– Contains 23 serotypes of pneumococcus(1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F).


  2. PCVs: The capsular PS is conjugated to a conventional or active carrier protein, for example:


  3. non-typable H. influenza (NTHi) toxoid or diphtheria/tetanus variant toxoid

    • PCV-10 (PHiD-CV) – It contains serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5 and 7F conjugated to NTHi protein D, tetanus toxoid and diphtheria toxoid. This vaccine provides cross protection against serotypes 6A and 19A. Originally, the experimental vaccine included 11 serotypes, yet the inclusion of serotype 3 was rejected due to a lack of inducible immunogenicity during clinical trials.[59] This vaccine has shown adequate immunological response in a three-dose primary series compared with the PCV-7. There is also immunological memory following primary immunisation with PCV-10
    • PCV-13 – It contains the capsular PS of PCV-7 serotypes and six additional serotypes (1, 3, 5, 6A, 7F and 19A). It is conjugated to cross-reactive material Corynebacterium diphtheria (CRM197)
    • 15-valent PCV contains PS from PCV-13 serotypes and two additional serotypes 22F and 33F conjugated to CRM197 and formulated on aluminium phosphate adjuvant. In animal model studies, post-vaccination antibody response was >10 fold higher compared to baseline for the eight additional PCV-7 serotypes.[60]


Pneumococcal vaccines included in different countries

Currently, vaccination with PCV is recommended for the NIP in most countries for the following groups: all children <23 months of age. Other eligible children include those between 24 and 59 months of age who are at a high risk of IPD including those who attend childcare centres; are of aboriginal origin and have sickle cell disease or other haemoglobinopathies, functional or anatomic asplenia, HIV infection or other immunocompromised conditions, chronic medical conditions or with cochlear implants.

As of March 2018, A total of 142 countries have introduced PCV into their NIP, while 17 countries have announced plans to introduce PCV into their NIP. Majority (103) of the countries were using PCV-13, whereas 31 countries uses PCV-10 and eight countries were using both (PCV-10 and 13).[61]

Pneumococcal vaccines - Indian scenario

PPSV-23 have proved to be less immunogenic in infants below 2 years of age. It has not been recommended for inclusion in the NIP including India.[62]

The two vaccines currently available in Indian pharmaceutical market are PCV-10 and PCV-13, with the protection level of 66% and 75% against disease-causing serotypes in India. Studies from Vellore, South India, demonstrated that PCV-10 and PCV-13 could provide protective coverage against 64% and 74.6% of serotypes responsible for IPD in Indian children, respectively.[35] In adults aged >65 years, PCV-13 and PPV-23 could provide protective coverage of 69.6% and 73.2% against serotypes responsible for IPD from a single-centric study in Vellore.[63] A multicentric IPD study on adults aged >60 years in India demonstrated PPSV-23 protective coverage as 83.3%.[64]

On May 13th, 2017, PCV-13 was launched by the Union health ministry of India under the UIP of selected Indian states of Himachal Pradesh and parts of Bihar (17 out of 38 districts) and Uttar Pradesh (6 out of 75 districts). This was followed with the introduction of PCV-13 in Madhya Pradesh and Rajasthan (9 out of 33 districts) in 2018. Eventually PCV-13 will be introduced in all states of India in phased manner in the coming years however timeline for PCV-13 introduction in other states is yet to be announced. The Global Alliance for Vaccine and Immunization (GAVI) will support PCV provision in India until 2021, and then after, PCV-13 cost in India will be borne by the government of India. India is introducing PCV-13 in (2 + 1) schedule with two primary doses at weeks 6 and 14, followed with a booster dose at 9th month.[65] While the doses and schedule were fixed for the states where PCV-13 is included in the NIP, there is no uniform guidelines available yet for larger other parts of the country. The Indian Academy of Paediatrics (IAP), recommends three primary doses of PCVs at six, 10 and 14 weeks followed with a booster dose at 15th months and a catch-up dose in 2-5-years of children. IAP also recommends PPSV-13 for children with high risk for pneumococcal infections.[66]

Pneumococcal vaccines - Active components and formulations

The PCV-10 contain 10 capsular PS from serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F conjugated to NTHi D protein, except serotype 19F conjugated to diphtheria toxoid and serotype 18C conjugated to tetanus toxoid. All conjugates are adsorbed to aluminium phosphate. The vaccine is provided in prefilled single-dose syringes with a LUER Lock slip tip. Latex is contained within the syringe component.

Each 0.5 mL of PCV-13 dose is formulated with 0.2 μg from each of the 12 serotypes and 4 μg of PS from serotype 6B individually conjugated to CRM197 carrier protein which contains 0.565 mg of aluminium phosphate adsorbent and is thimerosal free. The vaccine is administered intramuscularly and is available in single-dose, prefilled syringes that do not contain latex. Each dose contains succinic acid, polysorbate 80, aluminium phosphate and sodium chloride in water for injections.

Pneumococcal vaccines - Dose schedule

The current recommendations from WHO on PCVs is a schedule of three primary doses without a booster or two primary doses with a booster dose. One among these two options may be preferred based on local epidemiology or practical considerations, achieving high coverage with 3 doses. 3 + 1 schedule has been primarily used during the introduction of PCV-7 as well in PCV-13. Based on the current evidence and WHO recommendations most of the countries are using either 2 + 1 (57) or 3 + 0 (59) schedules. Only some countries (23) such as USA, Saudi Arabia, and Turkey continue to use 3 + 1 schedule. Canada is the only country using 2 + 1 and 3 + 1 schedules.[61]

Pneumococcal vaccines - Time taken, percentage and period of protection

In general, geometric mean concentrations of anticapsular antibodies increase by 5–10 folds after the initial series relative to the pre-immunisation concentrations. The antibody concentrations achieved are usually only sustained for a few months and decline thereafter to about the pre-immunisation levels. However, a dose of the pneumococcal vaccine, either PS or conjugate, administered during the 2nd year of life to children primed with any of the conjugates generally induces an approximately 10-fold increase in antibody concentrations.[67]

In a safety and immunogenicity study of PCV-10, for each vaccine serotype, the percentage of individuals with antibody concentrations ≥0.2 μg/ml was at least 93.2% following three primary doses and at least 97.4% post-booster; percentages with OPA titres ≥8 were at least 91.7% post-booster. After 2-dose catch-up, at least 94.3% of children had antibody concentrations ≥0.2 μg/ml against each serotype except 6B (84.3%); at least 95.2% had OPA titres ≥8 except against serotypes 1, 5 and 6B.[68]

All PCV-13 serotypes were immunogenic, with 88%–98% of infants achieving antibody concentrations of 0.35 μg/mL (protective) to shared PCV-7 serotypes. For the six additional serotypes, 97%–100% of PCV-13-vaccinated infants had non-inferiority criterion (i.e. achieving an IgG serum concentration of >0.35 μg/ml) 1 month after the third dose of PCV-13. However the level of functional antibody as defined by an OPA titre of >1:8 was met for all the 13 serotypes.[69]

Pneumococcal vaccines - Side effects

The most common adverse reactions, reported in >10% of children vaccinated with PPSV-23 in clinical trials, were as follows: injection-site pain/soreness/tenderness (60.0%), injection-site swelling/induration (20.3%), headache (17.6%), injection-site erythema (16.4%), asthenia/fatigue (13.2%) and myalgia (11.9%). Serious adverse experiences within 14 days after PPSV-23 included angina pectoris, heart failure, chest pain, ulcerative colitis, depression and headache/tremor/stiffness/sweating.

An increase in injection-site reactions was reported in children >12 months of age compared to the rates observed in infants during the primary series of PCV-10. The most common adverse reactions observed after primary vaccination were redness at the injection site and irritability which occurred after 38.3% and 52.3% of all doses, respectively. Following booster vaccination, these adverse reactions occurred at 52.6% and 55.4%, respectively. The majority of these reactions included mild fever, occasional drowsiness and loss of appetite, and these were not long lasting. The PCV-13 also had similar mild adverse effects.

Pneumococcal vaccines - Challenges

In the short time that the PCVs has been introduced into the immunisation programme, globally, the potential to control pneumococcal disease in young children has increased dramatically. Despite vaccines, antibiotic prophylaxis continues to play a major role in the protection of immunocompromised children. It is not certain whether the use of PCVs will decrease the need for antibiotic prophylaxis in future.

Further studies of pneumococcal vaccines are needed, including studies of the optimal dosage schedules for safety and efficacy for the administration of PCVs and PPSV-23 for healthy and high-risk children older than 24 months. Safety, immunogenicity and efficacy data are needed for conjugate vaccines used in children with late-acquired immune deficiencies and splenectomised individuals. Serologic correlates of protection have been proposed based on experimental models and extrapolated from similar (e.g. Hib) encapsulated organisms. Better-defined correlates of immunity could facilitate the licensure and approval of future PCVs. In addition, there is a need for continuous surveillance of the causative serotypes of pneumococci involved in pneumococcal disease, particularly as the number of children who receive pneumococcal vaccines increases. Role of children in transmitting infections to the adult vulnerable population, especially those with HIV, needs to be studied. Nasopharynx as a niche for carriage of multiple serotypes as documented by post 5-PCV programme in Gambia and 9-PCV in Sweto, South Africa, and antimicrobial resistance in the persistence of infection and serotype distribution throw up a challenge to pneumococcal vaccines.[70]

Disease with replacement serotypes could be a significant problem and requires continues surveillance to track emerging non-vaccine serotypes. Safety and immunogenicity studies of combinations of PCVs with other PS conjugates (e.g. Hib and  Neisseria More Details meningitidis) or other childhood live and inactivated vaccines are needed as well to facilitate the administration of fewer doses of vaccines at immunisation visits. Besides, introduction of these vaccines in the NIP of developing countries including India has been hindered by the cost of the vaccines, paucity of data on disease burden in the population and targeting population group for vaccines.[71],[72]

Pneumococcal vaccines - How far we have moved since licensure?

Post-licensure surveillance has demonstrated declines in the incidence of meningitis, bacteraemic pneumonia and bacteraemia without a focus on the paediatric age. Rates of hospitalisation due to IPD have declined. According to the Centers for Disease Control and Prevention, US, Active Bacterial Core surveillance system, from 1998 to 1999 through 2007, overall and PCV-7 serotype-specific IPD rates decreased by 45% (from 24.4 to 13.5 cases/100,000 population) and 94% (from 15.5 to 1.0 cases/100,000 population), respectively. The largest reductions in IPD incidence have been observed in children aged <5 years, the target population of the vaccination programme, with remarkable reductions in all and PCV-7 serotype-specific IPD rates of 76% and >95%, respectively.[58]

Achieving and maintaining a high coverage of PCVs can further reduce IPD among children aged <5 years; post-licensure monitoring will help characterise the effectiveness of PCV-10/13 and track the potential change in disease burden caused by non PCV serotypes. Vaccines might also provide herd immunity, against the circulating antibiotic-resistant serotypes, covered by each formulation. Antibiotic use is reduced in immunised children, as suggested by studies from Israel and California.[73] This in turn will reduce the selection of antibiotic-resistant strains in immunised communities. Surveillance is needed to monitor the spread of antimicrobial resistance into non-vaccine serotypes, which may lead to a resurgence of resistance. Furthermore, surveillance serves as the cornerstone of vaccine introduction as it provides baseline data before vaccine introduction, local disease burden data including the serotypes. However, it poses challenges as there are multiple syndromes some of which are common, limited diagnostic capabilities and emergence of drug-resistant serotypes not included in the vaccine.

In response to the WHO Strategic Advisory Group of Experts (SAGE) recommendation that serotype replacement should be monitored following the introduction of PCVs, the WHO in collaboration with the accelerated vaccine introduction technical assistance consortium (AVITAC) conducted a systematic analysis of available data on pneumococcal serotype epidemiology following PCV-7 introduction. The purpose was to document the occurrence and extent of serotype replacement following PCV introduction, assess factors that may have contributed to serotype changes following PCV introduction and define important surveillance characteristics for monitoring serotype replacement. The conclusions were presented to SAGE in November 2011 where it was concluded that PCV introduction had resulted in overall IPD reductions in children under 5 years despite increases in the incidence of non-vaccine serotypes. SAGE, therefore, concluded that serotype replacement should not be an impediment to PCV introduction, and the observed increases in non-vaccine serotype IPD with the use of PCV-7 are likely to be mitigated by the use of PCVs with broader serotype coverage – such as PCV-10 and PCV-13.

Future vaccines

There is a need to look at other virulence factors which may be potential targets for vaccines to overcome the drawbacks of the current type-specific capsular PS vaccines. Future vaccines to prevent IPD are focusing on non-capsular candidate antigens common to all serotypes, namely neuraminidase, autolysin, pneumolysin, pneumococcal surface protein A (PspA) and surface adhesion (PsaA). They might induce a T-cell-dependent response with immunological memory. Intranasal immunisation and plasmid DNA vaccines with PspA showed protection in mouse model studies.[74],[75],[76] A review on vaccine impact on pneumococcal disease by Klugman KP highlights several pertinent issues which are (a) role of children in transmitting infections to the adult vulnerable population, especially those with HIV; (b) nasopharynx as a niche for carriage of multiple serotypes as documented by post 5-PCV programme in Gambia and 9-PCV in Sweto, South Africa and (c) antimicrobial resistance in the persistence of infection and serotype distribution of pneumococci.[70] Increase in serotype 19A, which is a drug-resistant strain, in invasive disease, has led to the speculation that selection pressure of antibiotics and vaccination has led to the emergence of antibiotic-resistant non-vaccine serotypes. On the positive side of the vaccine is the reduction of secondary bacterial pneumonia in children with viral pneumonia following the introduction of PCV. Speculation that pneumococcus may have a role in the acute episodes of pneumonia in children with tuberculosis who get admitted to hospitals also needs to be studied. Pneumococcal vaccines which have proved to be beneficial in the developed countries need further studies in the developing countries by incorporating prevalent serotypes .[77] There is also a need to look at other virulence factors which may be potential targets for vaccines to overcome the drawbacks of the current type-specific capsular PS vaccines.

Acknowledgement

The authors thank the staff and participants of the ASIP and BASIS study for their support and contribution to the review. The scientific inputs provided by Dr. A. George Vasanthan, IDTRC, CMC Vellore is gratefully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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2004 - Indian Journal of Medical Microbiology
Published by Wolters Kluwer - Medknow

Online since April 2001, new site since 1st August '04