http://orcid.org/0000-0003-4632-357X
ABSTRACT
Streptococcus pneumoniae infection is a major global public health concern in older adults, especially as life expectancy continues to increase in most countries, including India. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) with the ability to enhance immunity (immunologic memory) on natural exposure or revaccination has been shown to protect against community-acquired pneumonia and invasive pneumococcal disease in adults 65 years of age and older. An unconjugated 23-valent pneumococcal polysaccharide vaccine has been available for decades; however, data on protection against pneumonia are inconsistent. For the first time, a multicenter study has been conducted in India to assess the safety and immunogenicity of a single dose of PCV13 in adults aged 50 to 65 years. In this study, PCV13 elicited robust immune responses against all 13 pneumococcal serotypes as reflected by the magnitude of geometric mean fold rises (range, 6.6–102.7) in functional antibody levels from before to 1 month after vaccination. No serious adverse events occurred. These clinical trial findings support the safety and immunogenicity of PCV13 when administered to adults in India and indicate that a single dose of PCV13 has the potential to protect against vaccine-type pneumococcal disease in adults aged 50 to 65 years. ClinicalTrials.gov identifier: NCT02034877
Introduction
Streptococcus pneumoniae infection is a major global public health concern in older adults,Citation1,2 especially as life expectancy continues to increase in most countries,Citation3 including India.Citation4,5
In adults in India, S pneumoniae has been identified as the most common pathogen causing community-acquired pneumonia (CAP)Citation6 and bacterial meningitis.Citation4,7 Invasive pneumococcal disease (IPD) in the region is also associated with high mortality, despite treatment in hospital settings.Citation4,6 Globally, increasing rates of resistance to antibiotics, including penicillin, erythromycin, cotrimoxazole, and chloramphenicol, and multidrug-resistant isolates have been observed.Citation1,7 Cotrimoxazole resistance rates in India have been reported to be comparably higher than those of other antibiotics.Citation4
In India, pneumococcal conjugate vaccines (PCVs) are available for young children but are not to date included in their national immunization program.Citation8,9 For adults, a 23-valent pneumococcal polysaccharide vaccine (PPSV23) is availableCitation9; however, routine use of PPSV23 is not generally recommended by the Expert Group of the Association of Physicians in India due to a lack of evidence to support its efficacy against pneumonia IPD in high-risk populations, such as adults aged ≥ 65 years, and routine administration of PPSV23 in adults in India is not predicted to be cost-effective.Citation10,11 Additionally, the duration of protection of PPSV23 is limited to 5 years, with a need for revaccination,112 and with the exception of certain immunocompromised populations who are at increased risk of IPD, revaccination is not recommended.Citation1,13
The 13-valent pneumococcal conjugate vaccine (PCV13), which has recently been licensed in India for adults aged ≥ 50 years, includes serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Among adults in India, the most common circulating S pneumoniae serotypes include 1, 3, 4, 5, 6, 7, 8, 12, 14, 15, 16, and 19.Citation4,7,14-17 PPSV23 includes all PCV13 serotypes, except 6A, and serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F. In contrast to PPSV23, PCV13 is manufactured by conjugating the capsular saccharides of S pneumoniae to an immunogenic protein carrier (CRM197) to elicit a T-cell–dependent immune response.Citation18,19 Because T cells provide the signals required for the generation of B-cell memory, PCV13 has the potential to elicit a memory response with rapid mobilization of antibody-forming cells on subsequent natural exposure or on revaccination.Citation18,19 The efficacy of PCV13 against vaccine-type CAP (including nonbacteremic) and IPD in adults aged ≥ 65 years is supported by the findings from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA).Citation20
Recently, the Advisory Committee on Immunization Practices (ACIP) in the United States recommended that all adults ≥ 65 years of age receive PCV13 followed by PPSV23 at an interval of at least 1 year following the PCV13 dose.Citation21,22 These recommendations were driven by clinical data showing the efficacy of PCV13 against CAP and IPD in the elderly, the remaining disease burden caused by serotypes in PCV13, and the greater number of serotypes covered by PPSV23 for possible additional protection against IPD.Citation21,22
The aim of the current study was to assess the safety and immunogenicity of PCV13 when administered to adults aged 50 to 65 years in India. This study was conducted as part of a postlicensure commitment by the New Drug Advisory Committee and the Drugs Controller General of India.
Results
Study population
A total of 1000 adults were enrolled, 999 were vaccinated, 993 (99.3%) completed the study, and 7 (0.7%) were withdrawn (loss to follow-up, n = 3 [0.3%]; withdrew consent, n = 3 [0.3%]; other reasons occurring before vaccination, n = 1 [0.1%]).
Demographic and baseline characteristics of the participants are summarized in . Of the 999 participants who were vaccinated, 58.6% were men, and the median age at vaccination was 57.4 years At baseline, 52.9% of participants reported a medical condition.
Table 1. Baseline demographic characteristics.
Of the 1000 enrolled participants, 400 were randomized to the immunogenicity subset; 388 were included in the immunogenicity analysis population, and 12 were excluded (not vaccinated, n = 1; blood samples not taken as required per protocol, n = 11). Demographic characteristics of the 388 participants included in the immunogenicity analysis population were comparable to that of the safety analysis population. No participant had received prior vaccination with PPSV23 or any other pneumococcal vaccine.
Safety
A summary of adverse events (AEs) occurring after vaccination is provided in . Seventy participants (7.0%) reported a total of 107 AEs. The most frequently reported AEs were vaccination site pain (4.6%) and pyrexia (2.2%); all other AEs were reported in less than 1.0% of participants. All AEs were mild to moderate in severity, and all had resolved by the end of the study. All but 4 AEs (cough, chronic obstructive pulmonary disease, viral infection, and vaccination site pain) were considered by the investigator as having a reasonable possibility of being related to PCV13. No deaths or serious AEs (SAEs) were reported, and no AE led to withdrawal of a participant from the study.
Table 2. Adverse events reported up to 1 month after PCV13 vaccination.
Immunogenicity
Analysis of immune responses as measured by opsonophagocytic activity (OPA) assay showed a statistically significant increase in OPA geometric mean titers (GMTs) for all 13 serotypes from before to approximately 1 month after vaccination with the lower limit of the 2-sided 95% CI for the geometric mean fold rise (GMFR) >1 ().
Table 3. Geometric mean fold rises of pneumococcal OPA GMTs before and 1 month after PCV13 vaccination.
A post hoc analysis of the immune responses by the 6 states in India where participants resided showed that OPA GMTs for all 13 serotypes were generally similar across 4 of the participating states both at baseline and 1 month after vaccination (Table S1). Two states (Tamil Nadu and Uttar Pradesh) had too few participants to infer similarity. Similarly, a post hoc analysis of immune responses by age showed that OPA GMTs for all 13 pneumococcal serotypes were similar between the 2 age groups (ie, 50 to 59 and 60 to 65 years) at baseline and 1 month after vaccination (Table S2).
In a post hoc analysis of immune responses by sex, OPA GMTs 1 month after vaccination were similar across the male and female subsets for 8 serotypes and statistically significantly lower for 5 serotypes in the male subset with the upper limit of the 2-sided 95% CI for the GMT ratio (males/females) <1 (Table S3). For the US study, OPA GMTs postvaccination were similar for 9 serotypes and statistically significantly lower in the male subset for 4 serotypes with the upper limit of the 2-sided 95% CI for the GMT ratio (males/females) <1. For the Mexico study, OPA GMTs postvaccination were similar for 11 serotypes and statistically significantly higher in the male subset for 2 serotypes with the lower limit of the 2-sided 95% CI for the GMT ratio (males/females) >1.
In , the reverse cumulative distribution curves (RCDCs) from this study for each of the 13 pneumococcal serotypes before and approximately 1 month after vaccination were compared with RCDCs from studies in similarly aged populations (50 to 64 years) in the United States and Mexico.Citation23,24 Compared with the US study population, RCDCs indicate higher antibody titers before vaccination and higher postvaccination immune responses in Indian participants for the majority of serotypes. Compared with the Mexico study population,Citation24 RCDCs indicate a trend toward higher antibody titers before vaccination for some serotypes, with higher postvaccination immune responses in the Indian participants for the majority of serotypes.
Figure 1. Reverse cumulative distribution curves of OPA antibody titers before and 1 month after administration of PCV13 in study populations of similar age in India, Mexico, and the United States. Vertical lines indicate serotype-specific LLOQ. LLOQ = lower limit of quantitation; OPA = opsonophagocytic activity; PCV13 = 13-valent pneumococcal conjugate vaccine.
Discussion
The findings from this study indicate that PCV13 is safe and well tolerated in adults aged 50 to 65 years in India. PCV13 elicited robust immune responses as indicated by the degree of the geometric mean fold rises (range, 6.6–102.7) of functional antibody GMTs before and approximately 1 month after PCV13 vaccination.
This study was conducted in 6 states in India (Andhra Pradesh, Gujarat, Karnataka, Maharashtra, Tamil Nadu, and Uttar Pradesh). No notable differences in immune responses (OPA GMTs) between 4 states were observed at baseline or 1 month after vaccination, while 2 states had too few participants to infer similarity. In addition, no statistically significant differences in immune responses were observed between age groups (50 to 59 years and 60 to 65 years) in the India study. This is in contrast to findings in the US study, in which the study population aged 50 to 59 years had statistically significantly higher immune responses (OPA GMTs) for the majority of serotypes compared with the population aged 60 to 64 years.Citation23
A comparison by sex in the India study showed similar immune responses between males and females for the majority of serotypes with statistically significantly lower OPA GMTs for 5 of the 13 serotypes in the male subset. Similar findings were found in the US study with statistically significantly lower OPA GMTs for 4 of the 13 serotypes in the male subset compared with the female subset. For the Mexico study, similar immune responses were also observed for the majority of serotypes, but OPA GMTs for 2 of the 13 serotypes were statistically significantly higher in the male subset compared with the female subset. Sex differences in antibody responses have been reported with several vaccines;Citation25 however, as our data have shown, any statistically significant differences observed in the male and female subsets have not been consistent across all vaccine antigens or populations. The cause of sex differences in immune responses is likely to be multifactorial.Citation25
Population differences in postvaccination immune responses between continents have been reported previously, with differing immune responses observed in populations from Asia compared with those from Europe and the United States.Citation26,27 RCDCs indicated higher baseline immune responses for some serotypes and higher postvaccination immune responses for the majority of serotypes in the study population in India compared with the study populations in the United StatesCitation23 and Mexico.Citation24 This may reflect a memory response corresponding to greater natural environmental antigen exposure of the population in India; however, genetic and other factors may also play a role. Of note, PCV13 is not part of the infant national immunization program in India,Citation8 so a reduction in circulating serotypes in the environment due to herd effects following immunization with PCV13 has not been observed.
Because there are limited existing data on pneumococcal conjugate vaccine safety and immunogenicity in adults from India, this study contributes to the knowledge base for PCV13 in this population. A limitation of this study is the lack of data on the effect of PCV13 vaccination on clinical outcomes. However, efficacy of PCV13 in adults aged ≥ 65 years has been demonstrated in the CAPiTA study, which demonstrated PCV13 to be efficacious against CAP and IPD.Citation20 This suggests that the immunogenicity responses observed in our study, which were higher than those observed in the CAPiTA study (Pfizer data on file), may correlate with vaccine efficacy observed in this population.
In conclusion, vaccination with PCV13 is safe and immunogenic in adults aged 50 to 65 years in India. In consideration of the robust immune responses observed in this population and efficacy data for PCV13 demonstrated in the CAPiTA trial in adults aged ≥ 65 years, PCV13 has the potential to protect against vaccine-serotype pneumococcal disease in the adult population in India. Whether a combined regimen of PCV13 followed by PPSV23 would be beneficial for Indian adults to expand serotype coverage to serotypes not included in PCV13 is subject to discussion by the recommending bodies in India. A combined regimen of PCV13 followed by PPSV23 is recommended by ACIP in the United States in adults aged ≥ 65 years and in persons aged ≥ 2 years who are at high risk for pneumococcal disease because of underlying medical conditions.Citation21,22 Such recommendations in India must take into account the risk of IPD and pneumonia in different age groups, underlying comorbidities, and the variability of serotype epidemiology in different geographical areas, where available.
Patients and methods
Study design and participants
This open-label, single-arm study (ClinicalTrials.gov identifier: NCT02034877) was conducted at 12 sites in 6 states throughout India. The states included (1) Maharashtra, where 6 sites enrolled 591 participants (2 sites in Nashik [n = 96 and n = 100], 2 sites in Pune [n = 87 and n = 80], and 1 site each in Mumbai [n = 34] and Nagpur [n = 194]); (2) Karnataka, where 2 sites enrolled 98 participants (1 site each in Bangalore [n = 45] and Hubli [n = 53]); (3) Uttar Pradesh, where 1 site (Varanasi) enrolled 34 participants; (4) Gujarat, where 1 site (Ahmedabad) enrolled 165 participants; (5) Tamil Nadu, where 1 site (Vellore) enrolled 25 participants; and (6) Andhra Pradesh, where 1 site (Visakhapatnam) enrolled 87 participants.
The safety of PCV13 in 1000 participants aged 50 to 65 years was assessed; immunogenicity was assessed in a subset of 400 participants. A cohort of 200 pediatric participants, aged 6 to 17 years, was also included in this study and will be reported separately.
Participants with preexisting stable disease, defined as disease not requiring a significant change in therapy or hospitalization for worsening disease 12 weeks before receipt of PCV13, were eligible. Individuals with a history of severe adverse reactions associated with a vaccine or vaccine component, immunocompromised individuals with known or suspected immunodeficiency or previously treated with immunosuppressive therapy, and those with a documented S pneumoniae infection in the past 5 years or prior pneumococcal vaccination within the last year were excluded.
This study was conducted in compliance with the ethical principles of the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines. All local regulatory requirements were also followed. Written informed consent and an audio/visual recording of the informed consent discussion, in accordance with requirements of the Indian Ministry of Health and Welfare, were obtained from all participants before enrollment and before performance of any study-related procedures. Government-issued photo identification of all the participants was verified, and photocopies of the identification were preserved.
Vaccines and administration
The 13-valent pneumococcal conjugate vaccine contains capsular polysaccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F (contains 2.2 μg of each saccharide, except for 4.4 μg of 6B) individually conjugated to CRM197, 5 mM succinate buffer, 0.85% sodium chloride, 0.02% polysorbate 80, and 0.125 mg aluminum as aluminum phosphate per 0.5-mL dose. PCV13 was manufactured by Wyeth, a Pfizer Company. The vaccine was supplied in single-dose syringes without preservatives and stored at temperatures between 2°C and 8°C. Participants received a single dose of PCV13 (0.5 mL) administered intramuscularly into the deltoid muscle.
Determination of sample size
A total of 1000 adults aged 50 to 65 years were included in the study, which provided a ≤ 5% chance of missing an AE experienced by ≥ 3 out of 1000 participants. A subset of 400 randomly selected individuals participated in the immunogenicity analysis. Sample-size estimation for the immunogenicity subset was based on GMTs calculated immediately before and approximately 1 month after PCV13 vaccination using data from a previous phase 3 US study of PCV13 in adults aged 60 to 64 years.Citation28 A sample of 360 evaluable participants provided ≥ 0.169 precision on the 2-sided 95% CI for OPA GMFRs for the 13 serotypes.
The evaluable immunogenicity analysis population included all participants who received the vaccination, had blood drawn within the specified time frame, had ≥ 1 valid assay result for the immunogenicity analysis, received no prohibited vaccines, and had no other major protocol violations.
Assessments
AEs were solicited by the investigator in response to nonspecific questions and recorded in an electronic AE case report form. AEs were collected from the time of signing of the informed consent up until 28 to 42 days after vaccination. The percentages of participants reporting AEs and SAEs within approximately 1 month after receiving PCV13 were determined.
The 400 individuals who participated in the immunogenicity analysis were selected using a continuously accessible randomization system. For this analysis, a blood sample (approximately 10 mL) was collected immediately before vaccination (baseline) and 1 month after vaccination. Antibody-mediated OPA against each of the 13 pneumococcal serotypes in PCV13 was measured using a serotype-specific microcolony OPA (mcOPA) assay, with results expressed as GMTs for each serotype. An OPA titer was defined as the interpolated reciprocal serum dilution that would result in the complement-mediated killing of 50% of the bacteria in each mcOPA assay. The lower limit of quantitation (LLOQ) in titers for each serotype-specific assay was set as follows: serotype 1, 18; serotype 3, 12; serotype 4, 21; serotype 5, 29; serotype 6A, 37; serotype 6B, 43; serotype 7F, 210; serotype 9V, 345; serotype 14, 35; serotype 18C, 31; serotype 19A, 18; serotype 19F, 48; and serotype 23F, 13. OPA titers greater than the LLOQ were considered accurate, and their quantitated values were reported. Titers less than the LLOQ or denoted below the limit of quantitation were set to 0.5 × LLOQ for analysis. Immunogenicity endpoints included serotype-specific OPA antibody titers at both visits (immediately before and approximately 1 month after vaccination) and serotype-specific fold rises in antibody titers from immediately before to approximately 1 month after vaccination. OPA assays from this PCV13 study and the comparator studies were performed in a central laboratory by the same sponsor.
Comparator study populations
The US and Mexico post hoc comparator studies enrolled PPSV23-naive study populations aged 50 to 64 years. The US study compared the safety and immunogenicity of PCV13 (aged 50–59 years, n = 403; aged 60–64 years, n = 417) versus PPSV23 (aged 60–64 years, n = 414).Citation23 The Mexico study assessed the safety and immunogenicity of PCV13 in participants aged 50 to 64 years (n = 161) and participants aged ≥ 65 years (n = 161).Citation24 Eligibility criteria for these study populations were similar to those in the India study. Serology was conducted by the same sponsor in a central laboratory.
Immunogenicity analysis
The endpoints for the study included measuring functional antibody OPA titers elicited by the 13 pneumococcal serotypes contained in PCV13 at 2 time points (ie, before and at 1 month [28–42 days] after vaccination). The serotype-specific OPA titers were logarithmically transformed for the analysis. The OPA GMTs were calculated at each time point. Two-sided 95% CIs were constructed by back transformation of the CIs based on the Student t distribution for the mean logarithm of the titers. For each serotype, GMFRs from before to 1 month after vaccination were computed, and 2-sided 95% CIs were constructed using logarithmically transformed assay results.
Post hoc analyses included GMTs before and 1 month after vaccination by states in India where participants resided. No formal comparisons between states were made. Post hoc analyses also included comparisons of the GMTs between age groups (50 to 59 vs 60 to 65 years) and between sex (male vs female) within this study. For comparisons, the GMT ratios were calculated by back transforming the mean difference between the groups on the logarithmic scale. The 95% CIs for the ratios are back transformations of a CI based on the Student t distribution for the mean difference of the logarithms of the measures. For comparisons between subsets, the immune responses were statistically significantly lower when the upper limit of the 2-sided 95% CI for the GMT ratio was <1 and were statistically significantly higher when the lower limit of the 2-sided 95% CI for the GMT ratio was >1.
Post hoc analyses also included comparisons of similarly aged populations (50 to 64 years) from studies in the United States and Mexico using RCDCs to graphically display the percentage of participants achieving a wide range of OPA titers for each of the 13 pneumococcal serotypes before and approximately 1 month after vaccination. In addition, as described above for the India study, post hoc comparisons of the postvaccination OPA GMTs between males and females were performed.
Disclosure of potential conflicts of interest
C Juergens, N Le Dren-Narayanin, MW Cutler, WC Gruber, DA Scott, and B Schmoele-Thoma are employees of Pfizer Inc. and may have stock or stock options. V Sundaraiyer is an employee of a Pfizer-contracted company. BB Solanki, MB Chopada, and P Supe received research support from Pfizer Inc.
Supplemental_Material.docx
Download MS Word (81.4 KB)Acknowledgments
The authors thank the B1851140 study group and the participants of this study. The authors thank Dr Canna Ghia and Dr Gautam Rambhad of Pfizer Global Vaccines for their input on epidemiologic data for India. Editorial support was provided by Tricia Newell, PhD, of Complete Healthcare Communications, LLC (Chadds Ford, PA). This work was funded by Pfizer Inc.
All authors participated in the preparation of this article and were involved in collecting and interpreting the data, drafting the article, or critically revising the article for important intellectual content. All authors gave final approval of the version to be submitted.
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