Immunogenicity and safety of a 10-valent pneumococcal conjugate vaccine administered as a 2 + 1 schedule to healthy infants in The Gambia: a single-centre, double-blind, active-controlled, randomised, phase 3 trial.

BACKGROUND: Three pneumococcal conjugate vaccines (PCVs) are currently licensed and WHO prequalified for supply by UN agencies. Here, we aimed to investigate the safety and immunogenicity of SIIPL-PCV compared with PHiD-CV and PCV13, when administered to infants according to a 2 + 1 schedule. METHODS: This single-centre, double-blind, active-controlled, randomised, phase 3 trial was done in Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine clinical trial facilities within two government health centres in the western region of The Gambia. Healthy, PCV-naive infants aged 6-8 weeks were enrolled if they weighed at least 3·5 kg and had no clinically significant health complaints, as determined by history and clinical examination. Eligible infants were randomly assigned (1:1:1) to receive either SIIPL-PCV, PHiD-CV, or PCV13 using permuted blocks of variable size. Parents and the trial staff assessing all study outcomes were masked to vaccine group. The first PCV vaccine was given with other routine Expanded Programme on Immunization vaccines when infants were aged 6-8 weeks (visit 1). At visit 2, routine vaccines alone (without a PCV) were administered. At visit 3, the second dose of the PCV was administered alongside other routine vaccines. At visit 4, a blood sample was collected. Visits 1-4 took place at intervals of 4 weeks. The booster PCV was administered at age 9-18 months (visit 5), with final follow-up 4 weeks after the booster (visit 6). The primary immunogenicity outcome compared the serotype-specific IgG geometric mean concentrations (GMCs) generated by SIIPL-PCV with those generated by PHiD-CV and PCV13, 4 weeks after the booster. We used descriptive 95% CIs without adjustment for multiplicity. Immunogenicity analyses were done in the per protocol population (defined as all children who received all the assigned study vaccines, who had an immunogenicity measurement available, and who had no protocol deviations that might interfere with the immunogenicity assessment). This trial was registered with the Pan African Clinical Trials Registry, PACTR201907754270299, and ClinicalTrials.gov, NCT03896477. FINDINGS: Between July 18 and Nov 14, 2019, 745 infants were assessed for study eligibility. Of these, 85 infants (11%) were ineligible and 660 (89%) were enrolled and randomly assigned to receive SIIPL-PCV (n=220), PHiD-CV (n=220), or PCV13 (n=220). 602 infants (91%) were included in the per protocol immunogenicity population. The median age at vaccination was 46 days (range 42-56). 342 infants (52%) were female and 318 (48%) were male. Post-booster serotype-specific IgG GMCs generated by SIIPL-PCV ranged from 1·54 µg/mL (95% CI 1·38-1·73) for serotype 5 to 12·46 µg/mL (11·07-14·01) for serotype 6B. Post-booster GMCs against shared serotypes generated by PHiD-CV ranged from 0·80 µg/mL (0·72-0·88) for serotype 5 to 17·31 µg/mL (14·83-20·20) for serotype 19F. Post-booster GMCs generated by PCV13 ranged from 2·04 µg/mL (1·86-2·24) for serotype 5 to 15·54 µg/mL (13·71-17·60) for serotype 6B. Post-booster IgG GMCs generated by SIIPL-PCV were higher than those generated by PHiD-CV for seven of the eight shared serotypes (1, 5, 6B, 7F, 9V, 14, and 23F). The GMC generated by serotype 19F was higher after PHiD-CV. The SIIPL-PCV to PHiD-CV GMC ratios for shared serotypes ranged from 0·64 (95% CI 0·52-0·79) for serotype 19F to 2·91 (2·47-3·44) for serotype 1. The serotype 1 GMC generated by SIIPL-PCV was higher than that generated by PCV13, whereas serotype 5, 6A, 19A, and 19F GMCs were higher after PCV13. The SIIPL-PCV to PCV13 GMC ratios ranged from 0·72 (0·60-0·87) for serotype 19A to 1·44 (1·23-1·69) for serotype 1. INTERPRETATION: SIIPL-PCV was safe and immunogenic when given to infants in The Gambia according to a 2 + 1 schedule. This PCV is expected to provide similar protection against invasive and mucosal pneumococcal disease to the protection provided by PCV13 and PHiD-CV, for which effectiveness data are available. Generating post-implementation data on the impact of SIIPL-PCV on pneumococcal disease endpoints remains important. FUNDING: Bill & Melinda Gates Foundation.

A Live Attenuated COVID-19 Candidate Vaccine for Children: Protection against SARS-CoV-2 Challenge in Hamsters.

Children are at risk of infection from severe acute respiratory syndrome coronavirus-2 virus (SARS-CoV-2) resulting in coronavirus disease (COVID-19) and its more severe forms. New-born infants are expected to receive short-term protection from passively transferred maternal antibodies from their mothers who are immunized with first-generation COVID-19 vaccines. Passively transferred antibodies are expected to wane within first 6 months of infant's life, leaving them vulnerable to COVID-19. Live attenuated vaccines, unlike inactivated or viral-protein-based vaccines, offer broader immune engagement. Given effectiveness of live attenuated vaccines in controlling infectious diseases such as mumps, measles and rubella, we undertook development of a live attenuated COVID-19 vaccine with an aim to vaccinate children beyond 6 months of age. An attenuated vaccine candidate (dCoV), engineered to express sub-optimal codons and deleted polybasic furin cleavage sites in the spike protein of the SARS-CoV-2 WA/1 strain, was developed and tested in hamsters. Hamsters immunized with dCoV via intranasal or intramuscular routes induced high levels of neutralizing antibodies and exhibited complete protection against the SARS-CoV-2 wild-type isolates, i.e., the Wuhan-like (USA-WA1/2020) and Delta variants (B.1.617.2) in a challenge study. In addition, the dCoV formulated with the marketed measles-rubella (MR) vaccine, designated as MR-dCoV, administered to hamsters via intramuscular route, also protected against both SARS-CoV-2 challenges, and dCoV did not interfere with the MR vaccine-mediated immune response. The safety and efficacy of the dCoV and the MR-dCoV against both variants of SARS-CoV-2 opens the possibility of early immunization in children without an additional injection.