Efficacy of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination against SARS-CoV-2 variants of concern: Final analysis of a randomized, placebo-controlled, phase 1b/2 study in South African adults (COV005).

COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults aged 18-65 years. South Africa's first, second, and third waves of SARS-CoV-2 infections were respectively driven by the ancestral SARS-CoV-2 virus (wild type, WT), and SARS-CoV-2 Beta and Delta VoCs. VE against asymptomatic and symptomatic infection was 90.6% for WT, 6.7% for Beta and 77.1% for Delta. No cases of severe COVID-19 were documented ahead of unblinding. Safety was consistent with the interim analysis, with no new safety concerns identified. Notably, South Africa's Delta wave occurred ≥ 9 months after primary series vaccination, suggesting that primary series AZD1222 vaccination offers a good durability of protection, potentially due to an anamnestic response. Clinical trial identifier: CT.gov NCT04444674.

Single priming and booster dose of ten-valent and 13-valent pneumococcal conjugate vaccines and Streptococcus pneumoniae colonisation in children in South Africa: a single-centre, open-label, randomised trial.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) immunisation has reduced vaccine-serotype colonisation and invasive pneumococcal disease in South Africa, providing the opportunity to consider transitioning from a two-dose (2 + 1) to one-dose (1 + 1) primary series and a booster dose. METHODS: In this single-centre, open-label, randomised trial done in South Africa, infants aged 35-49 days without HIV infection, without childhood immunisations except for BCG and polio, and with gestation age at delivery of at least 37 weeks of age, a birthweight of at least 2500 g, and weight of at least 3500 g at the time of enrolment were randomly assigned (1:1:1:1:1:1), through block randomisation (block size of 30), to receive a single priming dose of ten-valent PCV (PCV10) or 13-valent PCV (PCV13) at either 6 weeks (6-week 1 + 1 group) or 14 weeks (14-week 1 + 1 group), compared with two priming doses at 6 weeks and 14 weeks (2 + 1 group), followed by a booster dose at 9 months of age in all groups. The primary objective of the trial has been published previously. We report the secondary objective of the effect of alternative doses of PCV10 and PCV13 on serotype-specific Streptococcus pneumoniae colonisation at 9 months, 15 months, and 18 months of age and a further exploratory analysis in which we assessed non-inferiority of serotype-specific serum IgG geometric mean concentrations 1 month after the booster (10 months of age) and the percentage of participants with serotype-specific IgG titre above the putative thresholds associated with a risk reduction of serotype-specific colonisation between the 1 + 1 and 2 + 1 groups for both vaccines. Non-inferiority was established if the lower limit of the 95% CI for the difference between the proportion of participants (1 + 1 group vs 2 + 1 group) above the putative thresholds was greater than or equal to -10%. All analyses were done in the modified intention-to-treat population, which included all participants who received PCV10 or PCV13 according to assigned randomisation group and for whom laboratory results were available. The trial is registered with ClinicalTrials.gov, NCT02943902. FINDINGS: 1564 nasopharyngeal swabs were available for molecular serotyping from 600 infants who were enrolled (100 were randomly assigned to each of the six study groups) between Jan 9 and Sept 20, 2017. There was no significant difference in the prevalence of overall or non-vaccine serotype colonisation between all PCV13 or PCV10 groups. PCV13 serotype colonisation was lower at 15 months of age in the 14-week 1 + 1 group than in the 2 + 1 group (seven [8%] of 85 vs 17 [20%] of 87; odds ratio 0·61 [95% CI 0·38-0·97], p=0·037), but no difference was seen at 9 months (nine [11%] of 86 vs ten [11%] of 89; 0·92 [0·60-1·55], p=0·87) or 18 months (nine [11%] of 85 vs 11 [14%] of 87; 0·78 [0·45-1·22], p=0·61). Compared with the PCV13 2 + 1 group, both PCV13 1 + 1 groups did not meet the non-inferiority criteria for serotype-specific anti-capsular antibody concentrations above the putative thresholds purportedly associated with risk reduction for colonisation; however, the PCV10 14-week 1 + 1 group was non-inferior to the PCV10 2 + 1 group. INTERPRETATION: The serotype-specific colonisation data reported in this study together with the primary immunogenicity endpoints of the control trial support transitioning to a reduced 1 + 1 schedule in South Africa. Ongoing monitoring of colonisation should, however, be undertaken immediately before and after transitioning to a PCV 1 + 1 schedule to serve as an early indicator of whether PCV 1 + 1 could lead to an increase in vaccine-serotype disease. FUNDING: The Bill & Melinda Gates Foundation.

Effectiveness of Influenza Vaccination of Pregnant Women for Prevention of Maternal and Early Infant Influenza-Associated Hospitalizations in South Africa: A Prospective Test-Negative Study.

Background: Influenza vaccination during pregnancy reduces influenza-associated illness in the women and their infants, but effectiveness estimates against influenza-associated hospitalization are limited and lacking from settings with high human immunodeficiency virus (HIV) infection prevalence. We assessed the effect of maternal vaccination in HIV-uninfected women and women with HIV in preventing influenza-associated hospitalizations in infants and the women. Methods: During 2015-2018, influenza vaccination campaigns targeting pregnant women were augmented at selected antenatal clinics; these were coupled with prospective hospital-based surveillance for acute respiratory or febrile illness in infants aged <6 months and cardiorespiratory illness among pregnant or postpartum women. Vaccine effectiveness (VE) was assessed using a test-negative case-control study. Results: Overall, 71 influenza-positive and 371 influenza-negative infants were included in the analysis; mothers of 26.8% of influenza-positive infants were vaccinated during pregnancy compared with 35.6% of influenza-negative infants, corresponding to an adjusted VE (aVE) of 29.0% (95% confidence interval [CI], -33.6% to 62.3%). When limited to vaccine-matched strains, aVE was 65.2% (95% CI, 11.7%-86.3%). For maternal hospitalizations, 56 influenza-positive and 345 influenza-negative women were included in the analysis, with 28.6% of influenza-positive women being vaccinated compared with 38.3% of influenza-negatives, for an aVE of 46.9% (95% CI, -2.8% to 72.5%). Analysis restricted to HIV-uninfected women resulted in 82.8% (95% CI, 40.7%-95.0%) aVE. No significant aVE (-32.5% [95% CI, -208.7% to 43.1%]) was detected among women with HIV. Conclusions: Influenza vaccination during pregnancy prevented influenza-associated hospitalizations among young infants when infected with vaccine strains and among HIV-uninfected women.

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant.

BACKGROUND: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).