Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/µL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/µL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern.

Standardized Phylogenetic Classification of Human Respiratory Syncytial Virus below the Subgroup Level.

A globally implemented unified phylogenetic classification for human respiratory syncytial virus (HRSV) below the subgroup level remains elusive. We formulated global consensus of HRSV classification on the basis of the challenges and limitations of our previous proposals and the future of genomic surveillance. From a high-quality curated dataset of 1,480 HRSV-A and 1,385 HRSV-B genomes submitted to GenBank and GISAID (https://www.gisaid.org) public sequence databases through March 2023, we categorized HRSV-A/B sequences into lineages based on phylogenetic clades and amino acid markers. We defined 24 lineages within HRSV-A and 16 within HRSV-B and provided guidelines for defining prospective lineages. Our classification demonstrated robustness in its applicability to both complete and partial genomes. We envision that this unified HRSV classification proposal will strengthen HRSV molecular epidemiology on a global scale.

SARS-CoV-2 correlates of protection from infection against variants of concern.

Serum neutralizing antibodies (nAbs) induced by vaccination have been linked to protection against symptomatic and severe coronavirus disease 2019. However, much less is known about the efficacy of nAbs in preventing the acquisition of infection, especially in the context of natural immunity and against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune-escape variants. Here we conducted mediation analysis to assess serum nAbs induced by prior SARS-CoV-2 infections as potential correlates of protection against Delta and Omicron infections, in rural and urban household cohorts in South Africa. We find that, in the Delta wave, D614G nAbs mediate 37% (95% confidence interval: 34-40%) of the total protection against infection conferred by prior exposure to SARS-CoV-2, and that protection decreases with waning immunity. In contrast, Omicron BA.1 nAbs mediate 11% (95% confidence interval: 9-12%) of the total protection against Omicron BA.1 or BA.2 infections, due to Omicron's neutralization escape. These findings underscore that correlates of protection mediated through nAbs are variant specific, and that boosting of nAbs against circulating variants might restore or confer immune protection lost due to nAb waning and/or immune escape. However, the majority of immune protection against SARS-CoV-2 conferred by natural infection cannot be fully explained by serum nAbs alone. Measuring these and other immune markers including T cell responses, both in the serum and in other compartments such as the nasal mucosa, may be required to comprehensively understand and predict immune protection against SARS-CoV-2.

SARS-CoV-2 BA.4/5 infection triggers more cross-reactive FcγRIIIa signaling and neutralization than BA.1, in the context of hybrid immunity.

SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing and antibody-dependent cellular cytotoxic (ADCC) antibodies with variable cross-reactivity. Omicron BA.4/5 was approved for inclusion in bivalent vaccination boosters, and therefore the antigenic profile of antibodies elicited by this variant is critical to understand. Here, we investigate the ability of BA.4/5-elicited antibodies following the first documented (primary) infection (n = 13) or breakthrough infection after vaccination (n = 9) to mediate neutralization and FcγRIIIa signaling across multiple SARS-CoV-2 variants including XBB.1.5 and BQ.1. Using a pseudovirus neutralization assay and a FcγRIIIa crosslinking assay to measure ADCC potential, we show that unlike SARS-CoV-2 Omicron BA.1, BA.4/5 infection triggers highly cross-reactive functional antibodies. Cross-reactivity was observed both in the absence of prior vaccination and in breakthrough infections following vaccination. However, BQ.1 and XBB.1.5 neutralization and FcγRIIIa signaling were significantly compromised compared to other VOCs, regardless of prior vaccination status. BA.4/5 triggered FcγRIIIa signaling was significantly more resilient against VOCs (<10-fold decrease in magnitude) compared to neutralization (10- to 100-fold decrease). Overall, this study shows that BA.4/5 triggered antibodies are highly cross-reactive compared to those triggered by other variants. Although this is consistent with enhanced neutralization and FcγRIIIa signaling breadth of BA.4/5 vaccine boosters, the reduced activity against XBB.1.5 supports the need to update vaccines with XBB sublineage immunogens to provide adequate coverage of these highly antibody evasive variants. IMPORTANCE: The continued evolution of SARS-CoV-2 has resulted in a number of variants of concern. Of these, the Omicron sublineage is the most immune evasive. Within Omicron, the BA.4/5 sublineage drove the fifth wave of infection in South Africa prior to becoming the dominant variant globally. As a result this spike sequence was approved as part of a bivalent vaccine booster, and rolled out worldwide. We aimed to understand the cross-reactivity of neutralizing and Fc mediated cytotoxic functions elicited by BA.4/5 infection following infection or breakthrough infection. We find that, in contrast to BA.1 which triggered fairly strain-specific antibodies, BA.4/5 triggered antibodies that are highly cross-reactive for neutralization and antibody-dependent cellular cytotoxicity potential. Despite this cross-reactivity, these antibodies are compromised against highly resistant variants such as XBB.1.5 and BQ.1. This suggests that next-generation vaccines will require XBB sublineage immunogens in order to protect against these evasive variants.

SARS-CoV-2 humoral immunity in people living with HIV-1.

The effect of COVID-19 on the high number of immunocompromised people living with HIV-1 (PLWH), particularly in Africa, remains a critical concern. Here, we identify key areas that still require further investigation, by examining COVID-19 vaccine effectiveness, and understanding antibody responses in SARS-CoV-2 infection and vaccination in comparison with people without HIV-1 (PWOH). We also assess the potential impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in these individuals. Lastly, we discuss the consequences of persistent infection in PLWH (or other immunocompromised individuals), including prolonged shedding, increased viral diversity within the host, and the implications on SARS-CoV-2 evolution in Africa.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

Characteristics of infections with ancestral, Beta and Delta variants of SARS-CoV-2 in the PHIRST-C community cohort study, South Africa, 2020-2021.

BACKGROUND: Data on the characteristics of individuals with mild and asymptomatic infections with different SARS-CoV-2 variants are limited. We therefore compared the characteristics of individuals infected with ancestral, Beta and Delta SARS-CoV-2 variants in South Africa. METHODS: We conducted a prospective cohort study in a rural and an urban site during July 2020-August 2021. Mid-turbinate nasal swabs were collected twice-weekly from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time reverse transcription polymerase chain reaction (rRT-PCR). Differences in demographic and clinical characteristics, shedding and cycle threshold (Ct) value of infection episodes by variant were evaluated using multinomial regression. Overall and age-specific incidence rates of infection were compared by variant. RESULTS: We included 1200 individuals from 222 households and 648 rRT-PCR-confirmed infection episodes (66, 10% ancestral, 260, 40% Beta, 322, 50% Delta). Symptomatic proportion was similar for ancestral (7, 11%), Beta (44, 17%), and Delta (46, 14%) infections (p=0.4). After accounting for previous infection, peak incidence shifted to younger age groups in successive waves (40-59 years ancestral, 19-39 years Beta, 13-18 years Delta). On multivariable analysis, compared to ancestral, Beta infection was more common in individuals aged 5-12 years (vs 19-39)(adjusted odds ratio (aOR) 2.6, 95% confidence interval (CI)1.1-6.6) and PCR cycle threshold (Ct) value <30 (vs >35)(aOR 3.2, 95%CI 1.3-7.9), while Delta was more common in individuals aged <5 (aOR 6.7, 95%CI1.4-31.2) and 5-12 years (aOR 6.6 95%CI2.6-16.7)(vs 19-39) and Ct value <30 (aOR 4.5, 95%CI 1.3-15.5) and 30-35 (aOR 6.0, 95%CI 2.3-15.7)(vs >35). CONCLUSIONS: Consecutive SARS-CoV-2 waves with Beta and Delta variants were associated with a shift to younger individuals. Beta and Delta infections were associated with higher peak viral loads, potentially increasing infectiousness.

Beta-variant recombinant booster vaccine elicits broad cross-reactive neutralization of SARS-CoV-2 including Omicron variants.

Background: SARS-CoV-2 Omicron lineage contains variants with multiple sequence mutations relative to the ancestral strain particularly in the viral spike gene. These mutations are associated inter alia with loss of neutralization sensitivity to sera generated by immunization with vaccines targeting ancestral strains or prior infection with circulating (non-Omicron) variants. Here we present a comparison of vaccine formulation elicited cross neutralization responses using two different assay readouts from a subpopulation of a Phase II/III clinical trial. Methods: Human sera from a Phase II/III trial (NCT04762680) was collected and evaluated for neutralizing responses to SARS-CoV-2 spike antigen protein vaccines formulated with AS03 adjuvant, following a primary series of two-doses of ancestral strain vaccine in individuals who were previously unvaccinated or as an ancestral or variant strain booster vaccine among individuals previously vaccinated with the mRNA BNT162b2 vaccine. Results: We report that a neutralizing response to Omicron BA.1 is induced by the two-dose primary series in 89% of SARS-CoV-2-seronegative individuals. A booster dose of each vaccine formulation raises neutralizing antibody titers that effectively neutralizes Omicron BA.1 and BA.4/5 variants. Responses are highest after the monovalent Beta variant booster and similar in magnitude to human convalescent plasma titers. Conclusion: The findings of this study suggest the possibility to generate greater breadth of cross-neutralization to more recently emerging viral variants through use of a diverged spike vaccine in the form of a Beta variant booster vaccine.

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/µL. In PWOH and PWH with CD4 counts ≥200 cells/µL, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

Background: We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods: A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results: No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion: In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH).

SARS-CoV-2 genomic surveillance in wastewater as a model for monitoring evolution of endemic viruses.

As global SARS-CoV-2 burden and testing frequency have decreased, wastewater surveillance has emerged as a key tool to support clinical surveillance efforts. The aims of this study were to identify and characterize SARS-CoV-2 variants in wastewater samples collected from urban centers across South Africa. Here we show that wastewater sequencing analyses are temporally concordant with clinical genomic surveillance and reveal the presence of multiple lineages not detected by clinical surveillance. We show that wastewater genomics can support SARS-CoV-2 epidemiological investigations by reliably recovering the prevalence of local circulating variants, even when clinical samples are not available. Further, we find that analysis of mutations observed in wastewater can provide a signal of upcoming lineage transitions. Our study demonstrates the utility of wastewater genomics to monitor evolution and spread of endemic viruses.

Healthcare utilization during the first two waves of the COVID-19 epidemic in South Africa: A cross-sectional household survey.

Healthcare utilization surveys contextualize facility-based surveillance data for burden estimates. We describe healthcare utilization in the catchment areas for sentinel site healthcare facilities during the first year of the COVID-19 pandemic. We conducted a cross-sectional healthcare utilization survey in households in three communities from three provinces (KwaZulu-Natal, Western Cape and North West). Field workers administered structured questionnaires electronically with the household members reporting influenza-like illness (ILI) in the past 30 days or severe respiratory illness (SRI) since March 2020. Multivariable logistic regression was used to identify factors associated with healthcare utilization among individuals that reported illness. From November 2020 through April 2021, we enrolled 5804 households and 23,003 individuals. Any respiratory illness was reported by 1.6% of individuals; 0.7% reported ILI only, 0.8% reported SRI only, and 0.1% reported both ILI and SRI. Any form of medical care was sought by 40.8% (95% CI 32.9% - 49.6%) and 71.3% (95% CI 63.2% - 78.6%) of individuals with ILI and SRI, respectively. On multivariable analysis, respiratory illness was more likely to be medically attended for individuals at the Pietermaritzburg site (aOR 3.2, 95% CI 1.1-9.5, compared to Klerksdorp), that were underweight (aOR 11.5, 95% CI 1.5-90.2, compared to normal weight), with underlying illness (aOR 3.2, 95%CI 1.2-8.5), that experienced severe illness (aOR 4.8, 95% CI 1.6-14.3) and those with symptom duration of ≥10 days (aOR 7.9, 95% CI 2.1-30.2, compared to <5 days). Less than half of ILI episodes and only 71% of SRI episodes were medically attended during the first two COVID-19 waves in South Africa. Facility-based data may underestimate disease burden during the COVID-19 pandemic.

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.

Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa.

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.

Novavax NVX-COV2373 triggers neutralization of Omicron sub-lineages.

The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4, BA.5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies induced by vaccination with ancestral spike or infection with previously circulating variants. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine containing the ancestral spike sequence, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4/BA.5 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples respectively. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4/BA.5 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4/BA.5 is dominating in multiple locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 From Adult Index Cases With and Without Human Immunodeficiency Virus in South Africa, 2020-2021: A Case-Ascertained, Prospective, Observational Household Transmission Study.

BACKGROUND: In South Africa, 19% of adults are living with human immunodeficiency virus (HIV; LWH). Few data on the influence of HIV on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission are available. METHODS: We performed a case-ascertained, prospective household transmission study of symptomatic adult index SARS-CoV-2 cases LWH and not living with HIV (NLWH) and their contacts from October 2020 to September 2021. Households were followed up 3 times a week for 6 weeks to collect nasal swabs for SARS-CoV-2 testing. We estimated household cumulative infection risk (HCIR) and duration of SARS-CoV-2 positivity (at a cycle threshold value <30 as proxy for high viral load). RESULTS: HCIR was 59% (220 of 373), not differing by index HIV status (60% LWH vs 58% NLWH). HCIR increased with index case age (35-59 years: adjusted OR [aOR], 3.4; 95% CI, 1.5-7.8 and ≥60 years: aOR, 3.1; 95% CI, 1.0-10.1) compared with 18-34 years and with contacts' age, 13-17 years (aOR, 7.1; 95% CI, 1.5-33.9) and 18-34 years (aOR, 4.4; 95% CI, 1.0-18.4) compared with <5 years. Mean positivity was longer in cases LWH (adjusted hazard ratio, 0.4; 95% CI, .1-.9). CONCLUSIONS: Index HIV status was not associated with higher HCIR, but cases LWH had longer positivity duration. Adults aged >35 years were more likely to transmit and individuals aged 13-34 to be infected SARS-CoV-2 in the household. As HIV infection may increase transmission, health services must maintain HIV testing and antiretroviral therapy initiation.

Risk Factors for Severe Coronavirus Disease 2019 Among Human Immunodeficiency Virus-Infected and -Uninfected Individuals in South Africa, April 2020-March 2022: Data From Sentinel Surveillance.

Background: Data on risk factors for coronavirus disease 2019 (COVID-19)-associated hospitalization and mortality in high human immunodeficiency virus (HIV) prevalence settings are limited. Methods: Using existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalization and mortality. Results: From April 2020 through March 2022, severe acute respiratory syndrome coronavirus 2 was detected in 24.0% (660 of 2746) of outpatient and 32.5% (2282 of 7025) of inpatient cases. Factors associated with COVID-19-associated hospitalization included the following: older age (25-44 [adjusted odds ratio {aOR}= 1.8, 95% confidence interval (CI) = 1.1-2.9], 45-64 [aOR = 6.8, 95% CI = 4.2-11.0] and ≥65 years [aOR = 26.6, 95% CI = 14.4-49.1] vs 15-24 years); black race (aOR, 3.3; 95% CI, 2.2-5.0); obesity (aOR, 2.3; 95% CI, 1.4-3.9); asthma (aOR, 3.5; 95% CI, 1.4-8.9); diabetes mellitus (aOR, 5.3; 95% CI, 3.1-9.3); HIV with CD4 ≥200/mm3 (aOR, 1.5; 95% CI, 1.1-2.2) and CD4 <200/mm3 (aOR, 10.5; 95% CI, 5.1-21.6) or tuberculosis (aOR, 12.8; 95% CI, 2.8-58.5). Infection with Beta (aOR, 0.5; 95% CI, .3-.7) vs Delta variant and being fully vaccinated (aOR, 0.1; 95% CI, .1-.3) were less associated with COVID-19 hospitalization. In-hospital mortality was increased in older age (45-64 years [aOR, 2.2; 95% CI, 1.6-3.2] and ≥65 years [aOR, 4.0; 95% CI, 2.8-5.8] vs 25-44 years) and male sex (aOR, 1.3; 95% CI, 1.0-1.6) and was lower in Omicron-infected (aOR, 0.3; 95% CI, .2-.6) vs Delta-infected individuals. Conclusions: Active syndromic surveillance encompassing clinical, laboratory, and genomic data identified setting-specific risk factors associated with COVID-19 severity that will inform prioritization of COVID-19 vaccine distribution. Elderly people with tuberculosis or people with HIV, especially severely immunosuppressed, should be prioritized 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.

Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa.

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.