Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.

Pneumococcal disease is a major cause of morbidity and mortality in young children, particularly in the developing world. Vaccines are a critical strategy for protecting children from pneumococcal disease and licensed pneumococcal conjugate vaccines (PCVs) are having a significant impact on invasive pneumococcal disease and pneumococcal pneumonia throughout the world. Currently available PCVs do not, however, cover all pneumococcal serotypes and are complicated and relatively expensive to manufacture. While new PCV development is focused on either higher valency or more inherent affordability for developing countries, new vaccines are needed that offer serotype-independent protection. Vaccines containing proteins that are common to all pneumococcal serotypes could provide broad protection to children worldwide. Protein subunit and whole cell vaccines have advanced into Phase 1 and 2 clinical trials but face considerable challenges before they can become licensed and widely distributed.

Pneumococcal conjugate vaccines (PCVs) have proven to be the best way to prevent severe childhood pneumococcal disease but until recently have been difficult for many countries to afford sustainably. In 2008, the Serum Institute of India, Pvt. Ltd. and PATH entered into a collaboration, funded in part by the Bill & Melinda Gates Foundation, to respond to this problem by developing a PCV designed to be affordable, accessible, and protective against the pneumococcal serotypes causing the most morbidity and mortality in low- and middle-income countries. The resulting 10-valent PCV (PNEUMOSIL®) received World Health Organization prequalification in December 2019 – making it just the third PCV to be certified as an option for Gavi, the Vaccine Alliance-eligible countries – and is being made available at a Gavi price of US$2/dose. The task of developing a state-of-the-art, yet lower-priced, PCV required public-private collaboration across geographies and yielded a variety of successes and learnings useful to the vaccine development field. Key among the learnings were factors related to manufacturing strategy and optimization, serotype selection, flexibility, early risk detection and mitigation, partner trust and continuity across similar-class products, complementary business philosophies, and early clarity of purpose.

Group B streptococcus (GBS) is a major global cause of neonatal meningitis, sepsis and pneumonia, with an estimated 91,000 infant deaths per year and an additional 46,000 stillbirths. GBS infection in pregnancy is also associated with adverse maternal outcomes and preterm births. As such, the World Health Organization (WHO) prioritised the development of a GBS vaccine suitable for use in pregnant women and use in LMICs, where the burden of disease is highest. Several GBS vaccines are in clinical development. The WHO Defeating Meningitis by 2030 has set a target of 2026 for vaccine licensure. This 'Vaccine Value Profile' (VVP) for GBS is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations, and in collaboration with stakeholders from the WHO regions of AFR, AMR, EUR, WPR. All contributors have extensive expertise on various elements of the GBS VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

A more affordable pneumococcal conjugate vaccine (PCV) that provides comparable protection to current PCVs is needed to ensure sustainable access in resource-limited settings. Serum Institute of India Pvt. Ltd.'s PCV candidate (SIIPL-PCV) has the potential to meet this need as manufacturing efficiency has been optimized and the vaccine targets the most prevalent disease-causing serotypes in Africa and Asia. We report SIIPL-PCV's safety, tolerability, and immunogenicity in adults, toddlers, and infants in The Gambia. This phase 1/2, randomized, double-blind trial sequentially enrolled 34 PCV-naive adults (18-40 years old), 112 PCV (Prevenar 13® [PCV13])-primed toddlers (12-15 months old), and 200 PCV-naive infants (6-8 weeks old), who were randomized (1:1) to receive SIIPL-PCV or a licensed comparator vaccine. Infants received three-doses of SIIPL-PCV or PCV13 at 6, 10, and 14 weeks of age co-administered with routine Expanded Program on Immunization (EPI) vaccines. Reactogenicity was solicited through seven-days post-vaccination; unsolicited adverse events (AEs) were assessed throughout the study. The safety and immunogenicity of a matching booster at 10-14 months of age were evaluated in a subset of 96 infants. Immune responses were evaluated post-primary and pre- and post-booster vaccinations. Reactogenicity was primarily mild-to-moderate in severity. In infants, the most common solicited reactions were injection-site tenderness and fever, with no meaningful treatment-group differences. There were no serious or severe vaccine-related AEs and no meaningful trends in SAEs, vaccine-related AEs, or overall AEs. Infant post-primary seroresponse rates (IgG level ≥ 0.35 µg/mL) were ≥89% for all serotypes except 6A (79%) in the SIIPL-PCV group. IgG GMCs were >1 µg/mL for all serotypes in both SIIPL-PCV and PCV13 groups. Post-booster GMCs were comparable between groups. SIIPL-PCV was well-tolerated, had an acceptable safety profile, and was immunogenic for all vaccine serotypes. Results support the evaluation of SIIPL-PCV in a phase 3 non-inferiority trial. Clinicaltrials.gov: NCT02308540.

Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody ‘fingerprints’, responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV’s surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding to a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity.Clinical trial registration: The trial was registered with ClinicalTrials.gov with Identifier NCT01537185; the results are available from https://clinicaltrials.gov/ct2/show/results/NCT01537185.