Abstract：
BACKGROUND: Introduction of pneumococcal conjugate vaccines (PCVs) reduced the number of cases of pneumococcal disease (PD). However, there is an increase in clinical and economic burden of PD from serotypes that are not part of the existing pneumococcal vaccines, particularly impacting pediatric and elder population. In addition, the regions where the PCV is not available, the disease burden remains high. In this study, immunogenicity and safety of the BE\'s 14-valent PCV (PNEUBEVAX 14™; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) was evaluated in infants in comparison to licensed vaccine, Prevenar-13 (PCV-13).
METHODS: This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants at 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study.
RESULTS: The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13.
CONCLUSIONS: BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine. The study was prospectively registered with clinical trial registry of India - CTRI/2020/02/023129.
METHODS: This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants at 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study.
RESULTS: The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13.
CONCLUSIONS: BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine. The study was prospectively registered with clinical trial registry of India - CTRI/2020/02/023129.
摘要：
背景：引入肺炎球菌结合疫苗（PCV）减少了肺炎球菌疾病（PD）的病例数。然而,不属于现有肺炎球菌疫苗的血清型增加了PD的临床和经济负担，尤其影响儿科和老年人。此外,PCV不可用的区域，疾病负担仍然很高。在这项研究中,与许可疫苗相比，在婴儿中评估了含有两种其他流行病学重要血清型（22F和33F）的BE\的14价PCV（PNEUBEVAX14™；BE-PCV-14）的免疫原性和安全性。Prevenar-13（PCV-13）。
方法：这是一项关键的3期单盲随机对照研究，在印度的12个地点进行了6-8周大的健康婴儿，给药时间为6-10-14周，以评估候选BE-PCV-14的免疫原性非劣效性和安全性。总的来说,1290名婴儿同样随机接受BE-PCV-14或PCV-13。引起局部反应和系统性事件，不良事件（AE），严重不良事件（SAE），并记录医疗不良事件（MAAE）。通过调理吞噬活性（OPA）测量抗PnCPS（抗肺炎球菌荚膜多糖）IgG浓度和功能性抗体滴度来评估免疫原性，完成三个剂量时间表后一个月。在本研究中还评估了由血清型6B提供的对血清型6A的交叉保护。
结果：BE-PCV-14的安全性与PCV-13疫苗相当。大多数报告的AE本质上是轻度的。在两个治疗组中均未报告严重或严重的AE。对于BE-PCV-14中的12种常见血清型和另外的血清型(22F和33F),NI标准如WHOTRS-977所定义的证明。就BE-PCV-14的所有14种血清类型的IgG免疫应答而言,满足主要免疫原性终点。此外，相当比例的受试者（69％）血清转化为血清型6A，即使该抗原不存在于BE-PCV-14中。这表明BE-PCV-14的血清型6B交叉保护血清型6A。BE-PCV-14还引发与PCV-13共有的所有血清型相当的血清型特异性功能性OPA免疫应答。
结论：BE-PCV-14被发现是安全的，并诱导对所有14种血清型的稳健和功能性血清型特异性免疫应答。它还引发针对血清型6B的交叉保护性免疫应答。这些发现表明，BE-PCV-14可以安全地给予婴儿，并实现对由疫苗涵盖的血清型引起的肺炎球菌疾病的保护。该研究在印度临床试验注册中心（CTRI/2020/02/023129）进行了前瞻性注册。
方法：这是一项关键的3期单盲随机对照研究，在印度的12个地点进行了6-8周大的健康婴儿，给药时间为6-10-14周，以评估候选BE-PCV-14的免疫原性非劣效性和安全性。总的来说,1290名婴儿同样随机接受BE-PCV-14或PCV-13。引起局部反应和系统性事件，不良事件（AE），严重不良事件（SAE），并记录医疗不良事件（MAAE）。通过调理吞噬活性（OPA）测量抗PnCPS（抗肺炎球菌荚膜多糖）IgG浓度和功能性抗体滴度来评估免疫原性，完成三个剂量时间表后一个月。在本研究中还评估了由血清型6B提供的对血清型6A的交叉保护。
结果：BE-PCV-14的安全性与PCV-13疫苗相当。大多数报告的AE本质上是轻度的。在两个治疗组中均未报告严重或严重的AE。对于BE-PCV-14中的12种常见血清型和另外的血清型(22F和33F),NI标准如WHOTRS-977所定义的证明。就BE-PCV-14的所有14种血清类型的IgG免疫应答而言,满足主要免疫原性终点。此外，相当比例的受试者（69％）血清转化为血清型6A，即使该抗原不存在于BE-PCV-14中。这表明BE-PCV-14的血清型6B交叉保护血清型6A。BE-PCV-14还引发与PCV-13共有的所有血清型相当的血清型特异性功能性OPA免疫应答。
结论：BE-PCV-14被发现是安全的，并诱导对所有14种血清型的稳健和功能性血清型特异性免疫应答。它还引发针对血清型6B的交叉保护性免疫应答。这些发现表明，BE-PCV-14可以安全地给予婴儿，并实现对由疫苗涵盖的血清型引起的肺炎球菌疾病的保护。该研究在印度临床试验注册中心（CTRI/2020/02/023129）进行了前瞻性注册。
