Trends in Cases, Hospitalization and Mortality Related to the Omicron BA.4/BA.5 Sub-Variants in South Africa.

BACKGROUND: This study compared admission incidence risk across waves, and the risk of mortality in the Omicron BA.4/BA.5 wave, to the Omicron BA.1/BA.2 and Delta waves. METHODS: Data from South Africa's national hospital surveillance system, SARS-CoV-2 case linelist and Electronic Vaccine Data System were linked and analysed. Wave periods were defined when the country passed a weekly incidence of 30 cases/100,000 people. In-hospital case fatality ratios (CFR) in the Delta, Omicron BA.1/BA.2 and Omicron BA.4/BA.5 wave periods were compared by post-imputation random effect multivariable logistic regression models. RESULTS: The CFR was 25.9% (N = 37,538/144,778), 10.9% (N = 6,123/56,384) and 8.2% (N = 1,212/14,879) in the Delta, Omicron BA.1/BA.2, and Omicron BA.4/BA.5 waves respectively. After adjusting for age, sex, race, comorbidities, health sector and province, compared to the Omicron BA.4/BA.5 wave, patients had higher risk of mortality in the Omicron BA.1/BA.2 wave (adjusted odds ratio [aOR] 1.3; 95% confidence interval [CI] 1.2-1.4) and Delta (aOR 3.0; 95% CI 2.8-3.2) wave. Being partially vaccinated (aOR 0.9, CI 0.9-0.9), fully vaccinated (aOR 0.6, CI 0.6-0.7) and boosted (aOR 0.4, CI 0.4-0.5); and prior laboratory-confirmed infection (aOR 0.4, CI 0.3-0.4) were associated with reduced risks of mortality. CONCLUSION: Overall, admission incidence risk and in-hospital mortality, which had increased progressively in South Africa's first three waves, decreased in the fourth Omicron BA.1/BA.2 wave and declined even further in the fifth Omicron BA.4/BA.5 wave. Mortality risk was lower in those with natural infection and vaccination, declining further as the number of vaccine doses increased.

A cohort study of post-COVID-19 condition across the Beta, Delta, and Omicron waves in South Africa: 6-month follow-up of hospitalized and nonhospitalized participants.

OBJECTIVES: The study aimed to describe the prevalence of and risk factors for post-COVID-19 condition (PCC). METHODS: This was a prospective, longitudinal observational cohort study. Hospitalized and nonhospitalized adults were randomly selected to undergo telephone assessment at 1, 3, and 6 months. Participants were assessed using a standardized questionnaire for the evaluation of symptoms and health-related quality of life. We used negative binomial regression models to determine factors associated with the presence of ≥1 symptoms at 6 months. RESULTS: A total of 46.7% of hospitalized and 18.5% of nonhospitalized participants experienced ≥1 symptoms at 6 months (P ≤0.001). Among hospitalized people living with HIV, 40.4% had persistent symptoms compared with 47.1% among participants without HIV (P = 0.108). The risk factors for PCC included older age, female sex, non-Black race, presence of a comorbidity, greater number of acute COVID-19 symptoms, hospitalization/COVID-19 severity, and wave period (lower risk of persistent symptoms for the Omicron compared with the Beta wave). There were no associations between self-reported vaccination status with persistent symptoms. CONCLUSION: The study revealed a high prevalence of persistent symptoms among South African participants at 6 months but decreased risk for PCC among participants infected during the Omicron BA.1 wave. These findings have serious implications for countries with resource-constrained health care systems.

Changing Epidemiology of COVID-19 in Children and Adolescents Over Four Successive Epidemic Waves in South Africa, 2020-2022.

BACKGROUND: South Africa experienced four waves of SARS-CoV-2 infection, dominated by Wuhan-Hu, Beta, Delta, and Omicron (BA.1/BA.2). We describe the trends in SARS-CoV-2 testing, cases, admissions, and deaths among children and adolescents in South Africa over successive waves. METHODS: We analyzed national SARS-CoV-2 testing, case, and admissions data from March 2020 to February 2022 and estimated cumulative rates by age group for each endpoint. The severity in the third versus the fourth wave was assessed using multivariable logistic regression. RESULTS: Individuals ≤18 years comprised 35% (21,008,060/60,142,978) of the population but only 12% (424,394/3,593,644) of cases and 6% (26,176/451,753) of admissions. Among individuals ≤18 years, infants had the highest admission (505/100,000) rates. Testing, case, and admission rates generally increased successively in the second (Beta) and third (Delta) waves among all age groups. In the fourth (Omicron BA.1/BA.2) wave, the case rate dropped among individuals ≥1 year but increased among those <1 year. Weekly admission rates for children <1 year (169/100,000) exceeded rates in adults (124/100,000) in the fourth wave. The odds of severe COVID-19 in all admitted cases were lower in the fourth wave versus the third wave in each age group, but they were twice as high in admitted cases with at least one comorbidity than those without. CONCLUSIONS: The admission rate for children <5 years was higher in the fourth wave than in previous waves, but the overall outcomes were less severe. However, children with at least one comorbidity had increased odds of severe disease, warranting consideration of prioritizing this group for vaccination.

Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages compared to BA.1 and Delta in South Africa.

Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. Here, we use the presence/absence of the S-gene target as a proxy for SARS-CoV-2 variant/lineage for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We link national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assess severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR 1.24, 95% CI 0.98-1.55) and severe outcome (aOR 0.72, 95% CI 0.41-1.26) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 showed similar severity to the BA.1 lineage and continued to show reduced clinical severity compared to the Delta variant.

Post-COVID-19 condition 3 months after hospitalisation with SARS-CoV-2 in South Africa: a prospective cohort study.

BACKGROUND: Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk. METHODS: In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC. FINDINGS: Of 241 159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04-1·38) and admission to an intensive care unit (1·17, 1·01-1·37). INTERPRETATION: Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC. FUNDING: Bill & Melinda Gates Foundation, UK Foreign, Commonwealth & Development Office, and Wellcome.

Clinical severity of COVID-19 in patients admitted to hospital during the omicron wave in South Africa: a retrospective observational study.

BACKGROUND: Up to the end of January, 2022, South Africa has had four recognisable COVID-19 pandemic waves, each predominantly dominated by one variant of concern: the ancestral strain with an Asp614Gly mutation during the first wave, the beta variant (B.1.351) during the second wave, the delta variant (B.1.617.2) during the third wave, and lastly, the omicron variant (B.1.1.529) during the fourth wave. We aimed to assess the clinical disease severity of patients admitted to hospital with SARS-CoV-2 infection during the omicron wave and compare the findings with those of the preceding three pandemic waves in South Africa. METHODS: We defined the start and end of each pandemic wave as the crossing of the threshold of weekly incidence of 30 laboratory-confirmed SARS-CoV-2 cases per 100 000 population. Hospital admission data were collected through an active national COVID-19-specific surveillance programme. We compared disease severity across waves by post-imputation random effect multivariable logistic regression models. Severe disease was defined as one or more of the following: acute respiratory distress, receipt of supplemental oxygen or mechanical ventilation, admission to intensive care, or death. FINDINGS: We analysed 335 219 laboratory-confirmed SARS-CoV-2 hospital admissions with a known outcome, constituting 10·4% of 3 216 179 cases recorded during the four waves. During the omicron wave, 52 038 (8·3%) of 629 617 cases were admitted to hospital, compared with 71 411 (12·9%) of 553 530 in the Asp614Gly wave, 91 843 (12·6%) of 726 772 in the beta wave, and 131 083 (10·0%) of 1 306 260 in the delta wave (p<0·0001). During the omicron wave, 15 421 (33·6%) of 45 927 patients admitted to hospital had severe disease, compared with 36 837 (52·3%) of 70 424 in the Asp614Gly wave, 57 247 (63·4%) of 90 310 in the beta wave, and 81 040 (63·0%) of 128 558 in the delta wave (p<0·0001). The in-hospital case-fatality ratio during the omicron wave was 10·7%, compared with 21·5% during the Asp614Gly wave, 28·8% during the beta wave, and 26·4% during the delta wave (p<0·0001). Compared with those admitted to hospital during the omicron wave, patients admitted during the other three waves had more severe clinical presentations (adjusted odds ratio 2·07 [95% CI 2·01-2·13] in the Asp614Gly wave, 3·59 [3·49-3·70] in the beta wave, and 3·47 [3·38-3·57] in the delta wave). INTERPRETATION: The trend of increasing cases and admissions across South Africa's first three waves shifted in the omicron wave, with a higher and quicker peak but fewer patients admitted to hospital, less clinically severe illness, and a lower case-fatality ratio compared with the preceding three waves. Omicron marked a change in the SARS-CoV-2 epidemic curve, clinical profile, and deaths in South Africa. Extrapolations to other populations should factor in differing vaccination and previous infection levels. FUNDING: National Institute for Communicable Diseases.

Identifying gaps in hand hygiene practice to support tailored target audience messaging in Soweto: A cross-sectional community survey.

Effective risk communication is essential for outbreak mitigation, as recently highlighted during the coronavirus disease 2019 (COVID-19) pandemic. Hand hygiene is one of the proposed public health interventions to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) acquisition and transmission along with social distancing, improved ventilation, environmental cleaning, and wearing of masks. Improving hand hygiene practices in the community requires an understanding of the socio-behavioural context. This cross-sectional community survey in Soweto identified gaps in hand hygiene, which can inform appropriate messaging at the community level. Only 42% of survey respondents practiced adequate hand hygiene. Tailored educational messaging should be targeted at young adults in particular, and the importance of soap for hand hygiene must be emphasised for all age groups. Risk communication should expand to focus on preventing multiple infectious diseases during and beyond the COVID-19 pandemic.

Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression.

BACKGROUND: Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination. METHODS: This study was designed as a systematic review and meta-regression. We did a systematic review of preprint and peer-reviewed published article databases from June 17, 2021, to Dec 2, 2021. Randomised controlled trials of COVID-19 vaccine efficacy and observational studies of COVID-19 vaccine effectiveness were eligible. Studies with vaccine efficacy or effectiveness estimates at discrete time intervals of people who had received full vaccination and that met predefined screening criteria underwent full-text review. We used random-effects meta-regression to estimate the average change in vaccine efficacy or effectiveness 1-6 months after full vaccination. FINDINGS: Of 13 744 studies screened, 310 underwent full-text review, and 18 studies were included (all studies were carried out before the omicron variant began to circulate widely). Risk of bias, established using the risk of bias 2 tool for randomised controlled trials or the risk of bias in non-randomised studies of interventions tool was low for three studies, moderate for eight studies, and serious for seven studies. We included 78 vaccine-specific vaccine efficacy or effectiveness evaluations (Pfizer-BioNTech-Comirnaty, n=38; Moderna-mRNA-1273, n=23; Janssen-Ad26.COV2.S, n=9; and AstraZeneca-Vaxzevria, n=8). On average, vaccine efficacy or effectiveness against SARS-CoV-2 infection decreased from 1 month to 6 months after full vaccination by 21·0 percentage points (95% CI 13·9-29·8) among people of all ages and 20·7 percentage points (10·2-36·6) among older people (as defined by each study, who were at least 50 years old). For symptomatic COVID-19 disease, vaccine efficacy or effectiveness decreased by 24·9 percentage points (95% CI 13·4-41·6) in people of all ages and 32·0 percentage points (11·0-69·0) in older people. For severe COVID-19 disease, vaccine efficacy or effectiveness decreased by 10·0 percentage points (95% CI 6·1-15·4) in people of all ages and 9·5 percentage points (5·7-14·6) in older people. Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time. INTERPRETATION: COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20-30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy. FUNDING: Coalition for Epidemic Preparedness Innovations.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa.

We provide two methods for monitoring reinfection trends in routine surveillance data to identify signatures of changes in reinfection risk and apply these approaches to data from South Africa's severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic to date. Although we found no evidence of increased reinfection risk associated with circulation of the Beta (B.1.351) or Delta (B.1.617.2) variants, we did find clear, population-level evidence to suggest immune evasion by the Omicron (B.1.1.529) variant in previously infected individuals in South Africa. Reinfections occurring between 1 November 2021 and 31 January 2022 were detected in individuals infected in all three previous waves, and there has been an increase in the risk of having a third infection since mid-November 2021.

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study.

BACKGROUND: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. METHODS: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021. FINDINGS: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity. INTERPRETATION: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity. FUNDING: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund.

Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial.

BACKGROUND: A monovalent, parenteral, subunit rotavirus vaccine was well tolerated and immunogenic in adults in the USA and in toddlers and infants in South Africa, but elicited poor responses against heterotypic rotavirus strains. We aimed to evaluate safety and immunogenicity of a trivalent vaccine formulation (P2-VP8-P[4],[6],[8]). METHODS: A double-blind, randomised, placebo-controlled, dose-escalation, phase 1/2 study was done at three South African research sites. Healthy adults (aged 18-45 years), toddlers (aged 2-3 years), and infants (aged 6-8 weeks, ≥37 weeks' gestation, and without previous receipt of rotavirus vaccination), all without HIV infection, were eligible for enrolment. In the dose-escalation phase, adults and toddlers were randomly assigned in blocks (block size of five) to receive 30 µg or 90 µg of vaccine, or placebo, and infants were randomly assigned in blocks (block size of four) to receive 15 µg, 30 µg, or 90 µg of vaccine, or placebo. In the expanded phase, infants were randomly assigned in a 1:1:1:1 ratio to receive 15 µg, 30 µg, or 90 µg of vaccine, or placebo, in block sizes of four. Participants, parents of participants, and clinical, data, and laboratory staff were masked to treatment assignment. Adults received an intramuscular injection of vaccine or placebo in the deltoid muscle on the day of randomisation (day 0), day 28, and day 56; toddlers received a single injection of vaccine or placebo in the anterolateral thigh on day 0. Infants in both phases received an injection of vaccine or placebo in the anterolateral thigh on days 0, 28, and 56, at approximately 6, 10, and 14 weeks of age. Primary safety endpoints were local and systemic reactions (grade 2 or worse) within 7 days and adverse events and serious adverse events within 28 days after each injection in all participants who received at least one injection. Primary immunogenicity endpoints were analysed in infants in either phase who received all planned injections, had blood samples analysed at the relevant timepoints, and presented no major protocol violations considered to have an effect on the immunogenicity results of the study, and included serum anti-P2-VP8 IgA, IgG, and neutralising antibody geometric mean titres and responses measured 4 weeks after the final injection in vaccine compared with placebo groups. This trial is registered with ClinicalTrials.gov, NCT02646891. FINDINGS: Between Feb 15, 2016, and Dec 22, 2017, 30 adults (12 each in the 30 µg and 90 µg groups and six in the placebo group), 30 toddlers (12 each in the 30 µg and 90 µg groups and six in the placebo group), and 557 infants (139 in the 15 µg group, 140 in the 30 µg group, 139 in the 90 µg group, and 139 in the placebo group) were randomly assigned, received at least one dose, and were assessed for safety. There were no significant differences in local or systemic adverse events, or unsolicited adverse events, between vaccine and placebo groups. There were no serious adverse events within 28 days of injection in adults, whereas one serious adverse event occurred in a toddler (febrile convulsion in the 30 µg group) and 23 serious adverse events (four in placebo, ten in 15 µg, four in 30 µg, and five in 90 µg groups) occurred among 20 infants, most commonly respiratory tract infections. One death occurred in an infant within 28 days of injection due to pneumococcal meningitis. In 528 infants (130 in placebo, 132 in 15 µg, 132 in 30 µg, and 134 in 90 µg groups), adjusted anti-P2-VP8 IgG seroresponses (≥4-fold increase from baseline) to P[4], P[6], and P[8] antigens were significantly higher in the 15 µg, 30 µg, and 90 µg groups (99-100%) than in the placebo group (10-29%; p<0·0001). Although significantly higher than in placebo recipients (9-10%), anti-P2-VP8 IgA seroresponses (≥4-fold increase from baseline) to each individual antigen were modest (20-34%) across the 15 µg, 30 µg, and 90 µg groups. Adjusted neutralising antibody seroresponses in infants (≥2·7-fold increase from baseline) to DS-1 (P[4]), 1076 (P[6]), and Wa (P[8]) were higher in vaccine recipients than in placebo recipients: p<0·0001 for all comparisons. INTERPRETATION: The trivalent P2-VP8 vaccine was well tolerated, with promising anti-P2-VP8 IgG and neutralising antibody responses across the three vaccine P types. Our findings support advancing the vaccine to efficacy testing. FUNDING: Bill & Melinda Gates Foundation.