The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults.

Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background.

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon.

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development.

The introduction of pneumococcal conjugate vaccines (PCV7, PCV10, PCV13) around the world has proved successful in preventing invasive pneumococcal disease. However, immunization against Streptococcus pneumoniae has led to serotype replacement by non-vaccine serotypes, including serotype 15A. Clonal complex 63 (CC63) is associated with many serotypes and has been reported in association with 15A after introduction of PCVs. A total of 865 CC63 isolates were included in this study, from the USA (n=391) and a global collection (n=474) from 1998-2019 and 1995-2018, respectively. We analysed the genomic sequences to identify serotypes and penicillin-binding protein (PBP) genes 1A, 2B and 2X, and other resistance determinants, to predict minimum inhibitory concentrations (MICs) against penicillin, erythromycin, clindamycin, co-trimoxazole and tetracycline. We conducted phylogenetic and spatiotemporal analyses to understand the evolutionary history of the 15A-CC63 sub-lineage. Overall, most (89.5 %, n=247) pre-PCV isolates in the CC63 cluster belonged to serotype 14, with 15A representing 6.5 % of isolates. Conversely, serotype 14 isolates represented 28.2 % of post-PCV CC63 isolates (n=618), whilst serotype 15A isolates represented 65.4 %. Dating of the CC63 lineage determined the most recent common ancestor emerged in the 1980s, suggesting the 15A-CC63 sub-lineage emerged from its closest serotype 14 ancestor prior to the development of pneumococcal vaccines. This sub-lineage was predominant in the USA, Israel and China. Multidrug resistance (to three or more drug classes) was widespread among isolates in this sub-lineage. We show that the CC63 lineage is globally distributed and most of the isolates are penicillin non-susceptible, and thus should be monitored.

Human immunodeficiency virus (HIV) infected adults are at a higher risk of pneumococcal colonisation and disease, even while receiving antiretroviral therapy (ART). To help evaluate potential indirect effects of vaccination of HIV-infected adults, we assessed whether HIV-infected adults disproportionately contribute to household transmission of pneumococci. We constructed a hidden Markov model to capture the dynamics of pneumococcal carriage acquisition and clearance observed during a longitudinal household-based nasopharyngeal swabbing study, while accounting for sample misclassifications. Households were followed-up twice weekly for approximately 10 months each year during a three-year study period for nasopharyngeal carriage detection via real-time PCR. We estimated the effect of participant's age, HIV status, presence of a HIV-infected adult within the household and other covariates on pneumococcal acquisition and clearance probabilities. Of 1,684 individuals enrolled, 279 (16.6%) were younger children (<5 years-old) of whom 4 (1.5%) were HIV-infected and 726 (43.1%) were adults (≥18 years-old) of whom 214 (30.4%) were HIV-infected, most (173, 81.2%) with high CD4+ count. The observed range of pneumococcal carriage prevalence across visits was substantially higher in younger children (56.9-80.5%) than older children (5-17 years-old) (31.7-50.0%) or adults (11.5-23.5%). We estimate that 14.4% (95% Confidence Interval [CI]: 13.7-15.0) of pneumococcal-negative swabs were false negatives. Daily carriage acquisition probabilities among HIV-uninfected younger children were similar in households with and without HIV-infected adults (hazard ratio: 0.95, 95%CI: 0.91-1.01). Longer average carriage duration (11.4 days, 95%CI: 10.2-12.8 vs 6.0 days, 95%CI: 5.6-6.3) and higher median carriage density (622 genome equivalents per millilitre, 95%CI: 507-714 vs 389, 95%CI: 311.1-435.5) were estimated in HIV-infected vs HIV-uninfected adults. The use of ART and antibiotics substantially reduced carriage duration in all age groups, and acquisition rates increased with household size. Although South African HIV-infected adults on ART have longer carriage duration and density than their HIV-uninfected counterparts, they show similar patterns of pneumococcal acquisition and onward transmission.

We aimed to describe the prevalence of human respiratory syncytial virus (HRSV) and evaluate associations between HRSV subgroups and/or genotypes and epidemiologic characteristics and clinical outcomes in patients hospitalized with severe respiratory illness (SRI).

Data on influenza community burden and transmission are important to plan interventions especially in resource-limited settings. However, data are limited, particularly from low-income and middle-income countries. We aimed to evaluate the community burden and transmission of influenza in a rural and an urban setting in South Africa.

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the USA, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identified a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last of which resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease, as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development.

Globally, over 400,000 neonatal deaths in 2015 were attributed to sepsis, however, the incidence and etiologies of these infections are largely unknown in low-middle income countries. We aimed to determine incidence and etiology of community-acquired early-onset (<72 hours age) sepsis (EOS) using culture and molecular diagnostics.

Pertussis remains a public health concern in South Africa, with an increase in reported cases and outbreaks in recent years. Whole genome sequencing was performed on 32 Bordetella pertussis isolates sourced from three different surveillance programmes in South Africa between 2015 and 2019. Genome sequences were characterized using multilocus sequence typing, vaccine antigen genes (ptxP, ptxA, ptxB, prn and fimH) and overall genome structure. All isolates were sequence type 2 and harboured the pertussis toxin promoter allele ptxP3. The dominant genotype was ptxP3-ptxA1-ptxB2-prn2-fimH2 (31/32, 96.9 %), with no pertactin-deficient or other mutations in vaccine antigen genes identified. Amongst 21 isolates yielding closed genome assemblies, eight distinct genome structures were detected, with 61.9 % (13/21) of the isolates exhibiting three predominant structures. Increases in case numbers are probably not due to evolutionary changes in the genome but possibly due to other factors such as the cyclical nature of B. pertussis disease, waning immunity due to the use of acellular vaccines and/or population immunity gaps.

By August 2021, South Africa experienced three SARS-CoV-2 waves; the second and third associated with emergence of Beta and Delta variants respectively.

South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. Propelled by increased transmissibility and immune escape properties, Omicron displaced other globally circulating variants within 3 months of its emergence. Due to limited testing, Omicron's attenuated clinical severity, and an increased risk of reinfection, the size of the Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood in South Africa and in many other countries. Using South African data from urban and rural cohorts closely monitored since the beginning of the pandemic, we analyzed sequential serum samples collected before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. Omicron BA.1/2 infection attack rates reached 65% (95% CI, 60% - 69%) in the rural cohort and 58% (95% CI, 61% - 74%) in the urban cohort, with repeat infections and vaccine breakthroughs accounting for >60% of all infections at both sites. Combined with previously collected data on pre-Omicron variant infections within the same cohorts, we identified 14 distinct categories of SARS-CoV-2 antigen exposure histories in the aftermath of the Omicron BA.1/2 wave, indicating a particularly fragmented immunologic landscape. Few individuals (<6%) remained naïve to SARS-CoV-2 and no exposure history category represented over 25% of the population at either cohort site. Further, cohort participants were more than twice as likely to get infected during the Omicron BA.1/2 wave, compared to the Delta wave. Prior infection with the ancestral strain (with D614G mutation), Beta, and Delta variants provided 13% (95% CI, -21% - 37%), 34% (95% CI, 17% - 48%), and 51% (95% CI, 39% - 60%) protection against Omicron BA.1/2 infection, respectively. Hybrid immunity (prior infection and vaccination) and repeated prior infections (without vaccination) reduced the risks of Omicron BA.1/2 infection by 60% (95% CI, 42% - 72%) and 85% (95% CI, 76% - 92%) respectively. Reinfections and vaccine breakthroughs had 41% (95% CI, 26% - 53%) lower risk of onward transmission than primary infections. Our study sheds light on a rapidly shifting landscape of population immunity, along with the changing characteristics of SARS-CoV-2, and how these factors interact to shape the success of emerging variants. Our findings are especially relevant to populations similar to South Africa with low SARS-CoV-2 vaccine coverage and a dominant contribution of immunity from prior infection. Looking forward, the study provides context for anticipating the long-term circulation of SARS-CoV-2 in populations no longer naïve to the virus.

Serotype 1 is an important cause of invasive pneumococcal disease in South Africa and has declined following the introduction of the 13-valent pneumococcal conjugate vaccine in 2011. We genetically characterized 912 invasive serotype 1 isolates from 1989 to 2013. Simpson's diversity index (D) and recombination ratios were calculated. Factors associated with sequence types (STs) were assessed. Clonal complex 217 represented 96% (872/912) of the sampled isolates. Following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), ST diversity increased in children <5 years (D, 0.39 to 0.63, P = 0.002) and individuals >14 years (D, 0.35 to 0.54, P < 0.001): ST-217 declined proportionately in children <5 years (153/203 [75%] versus 21/37 [57%], P = 0.027) and individuals >14 years (242/305 [79%] versus 96/148 [65%], P = 0.001), whereas ST-9067 increased (4/684 [0.6%] versus 24/228 [11%], P < 0.001). Three subclades were identified within ST-217: ST-217C1 (353/382 [92%]), ST-217C2 (15/382 [4%]), and ST-217C3 (14/382 [4%]). ST-217C2, ST-217C3, and single-locus variant (SLV) ST-8314 (20/912 [2%]) were associated with nonsusceptibility to chloramphenicol, tetracycline, and co-trimoxazole. ST-8314 (20/912 [2%]) was also associated with increased nonsusceptibility to penicillin (P < 0.001). ST-217C3 and newly reported ST-9067 had higher recombination ratios than those of ST-217C1 (4.344 versus 0.091, P < 0.001; and 0.086 versus 0.013, P < 0.001, respectively). Increases in genetic diversity were noted post-PCV13, and lineages associated with antimicrobial nonsusceptibility were identified.

Describing contact patterns is crucial to understanding infectious disease transmission dynamics and guiding targeted transmission mitigation interventions. Data on contact patterns in Africa, especially South Africa, are limited. We measured and compared contact patterns in a rural and urban community, South Africa. We assessed participant and contact characteristics associated with differences in contact rates.

A group of Victoria lineage influenza B viruses with a two amino acid deletion in the hemagglutinin (HA) at residues K162 and N163, was detected during the 2016 to 2017 Northern Hemisphere influenza season and continues to spread geographically. We describe the first identification of viruses with these deletions from South Africa in 2018.

We reported tet(S/M) in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions.

We investigated an outbreak of influenza-like illness (ILI) at a boarding school in Eastern Cape Province, South Africa. We aimed to confirm the etiological agent, estimate attack rates and identify risk factors for illness.

The pneumococcus produces a polysaccharide capsule, encoded by the cps locus, that provides protection against phagocytosis and determines serotype. Nearly 100 serotypes have been identified with new serotypes still being discovered, especially in previously understudied regions. Here we present an analysis of the cps loci of more than 18  000 genomes from the Global Pneumococcal Sequencing (GPS) project with the aim of identifying novel cps loci with the potential to produce previously unrecognized capsule structures. Serotypes were assigned using whole genome sequence data and 66 of the approximately 100 known serotypes were included in the final dataset. Closer examination of each serotype's sequences identified nine putative novel cps loci (9X, 11X, 16X, 18X1, 18X2, 18X3, 29X, 33X and 36X) found in ~2.6  % of the genomes. The large number and global distribution of GPS genomes provided an unprecedented opportunity to identify novel cps loci and consider their phylogenetic and geographical distribution. Nine putative novel cps loci were identified and examples of each will undergo subsequent structural and immunological analysis.

South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. However, the size of its Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood. We analyzed sequential serum samples collected through a prospective cohort study before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. We found that the Omicron BA.1/2 wave infected more than half of the cohort population, with reinfections and vaccine breakthroughs accounting for > 60% of all infections in both rural and urban sites. After the Omicron BA.1/2 wave, we found few (< 6%) remained naïve to SARS-CoV-2 and the population immunologic landscape is fragmented with diverse infection/immunization histories. Prior infection with the ancestral strain, Beta, and Delta variants provided 13%, 34%, and 51% protection against Omicron BA.1/2 infection, respectively. Hybrid immunity and repeated prior infections reduced the risks of Omicron BA.1/2 infection by 60% and 85% respectively. Our study sheds light on a rapidly shifting landscape of population immunity in the Omicron era and provides context for anticipating the long-term circulation of SARS-CoV-2 in populations no longer naïve to the virus.