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.

Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants: study protocol for a phase I trial.

BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.

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.

Aberrant innate immune profile associated with COVID-19 mortality in Pretoria, South Africa.

The African continent reported the least number of COVID-19 cases and deaths of all the continents, although the exact reasons for this are still unclear. In addition, little is known about the immunological profiles associated with COVID-19 mortality in Africa. The present study compared clinical and immunological parameters, as well as treatment outcomes in patients admitted with COVID-19 in Pretoria, South Africa, to determine if these parameters correlated with mortality in this population. The in-hospital mortality rate for the cohort was 15.79%. The mortality rate in people living with HIV (PLWH) was 10.81% and 17.16% in people without HIV (p = 0.395). No differences in age (p = 0.099), gender (p = 0.127) or comorbidities were found between deceased patients and those who survived. All four of the PLWH who died had a CD4+ T-cell count <200 cells/mm3, a significantly higher HIV viral load than those who survived (p = 0.009), and none were receiving antiretroviral therapy. Seven of 174 (4%) patients had evidence of auto-antibodies neutralizing Type 1 interferons (IFNs). Two of the them died, and their presence was significantly associated with mortality (p = 0.042). In the adjusted model, the only clinical parameters associated with mortality were: higher fraction of inspired oxygen (FiO2) (OR: 3.308, p = 0.011) indicating a greater need for oxygen, high creatinine (OR: 4.424, p = 0.001) and lower platelet counts (OR: 0.203, p = 0.009), possibly secondary to immunothrombosis. Overall, expression of the co-receptor CD86 (p = 0.021) on monocytes and percentages of CD8+ effector memory 2 T-cells (OR: 0.45, p = 0.027) was lower in deceased patients. Decreased CD86 expression impairs the development and survival of effector memory T-cells. Deceased patients had higher concentrations of RANTES (p = 0.003), eotaxin (p = 0.003) and interleukin (IL)-8 (p < 0.001), all involved in the activation and recruitment of innate immune cells. They also had lower concentrations of transforming growth factor (TGF)-ß1 (p = 0.40), indicating an impaired anti-inflammatory response. The immunological profile associated with COVID-19 mortality in South Africa points to the role of aberrate innate immune responses.

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.

Evaluating the antibody response elicited by diverse HIV envelope immunogens in the African green monkey (Vervet) model.

African Green (Vervet) monkeys have been extensively studied to understand the pathogenesis of infectious diseases. Using vervet monkeys as pre-clinical models may be an attractive option for low-resourced areas as they are found abundantly and their maintenance is more cost-effective than bigger primates such as rhesus macaques. We assessed the feasibility of using vervet monkeys as animal models to examine the immunogenicity of HIV envelope trimer immunogens in pre-clinical testing. Three groups of vervet monkeys were subcutaneously immunized with either the BG505 SOSIP.664 trimer, a novel subtype C SOSIP.664 trimer, CAP255, or a combination of BG505, CAP255 and CAP256.SU SOSIP.664 trimers. All groups of vervet monkeys developed robust binding antibodies by the second immunization with the peak antibody response occurring after the third immunization. Similar to binding, antibody dependent cellular phagocytosis was also observed in all the monkeys. While all animals developed potent, heterologous Tier 1 neutralizing antibody responses, autologous neutralization was limited with only half of the animals in each group developing responses to their vaccine-matched pseudovirus. These data suggest that the vervet monkey model may yield distinct antibody responses compared to other models. Further study is required to further determine the utility of this model in HIV immunization studies.

Hemagglutinin stalk-specific Fc-mediated functions are associated with protection against influenza-illness after seasonal influenza vaccination in pregnant women.

BACKGROUND: Several influenza vaccine candidates aim to elicit antibodies against the conserved hemagglutinin stalk domain. Understanding the protective mechanism of these antibodies, which mediate broad neutralization and Fc-mediated functions, following seasonal vaccination is critical. METHODS: Plasma samples were obtained from a subset of pregnant women living with or without HIV-1 enrolled in a randomised trial (138 trivalent inactivated vaccine [TIV] and 145 placebo recipients). Twenty-three influenza-illness cases were confirmed within 6 months postpartum. We measured H1 stalk-specific antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and cellular cytotoxicity (ADCC) at enrolment and 1-month post-vaccination. The association between these Fc-mediated functions and protection against influenza-illness following vaccination was examined using multiple logistic regression analysis and risk reduction thresholds were defined by the score associated with the lowest odds of influenza-illness. RESULTS: Amongst TIV and placebo recipients, lower H1 stalk-specific ADCP and ADCD activity was detected for participants with confirmed influenza compared with individuals without confirmed influenza-illness 1-month post-vaccination. Pre-existing ADCP scores ≥250 reduced the odds of A/H1N1 infection (odds ratio 0.11; p=0.01) with an 83% likelihood of risk reduction. Following TIV, ADCD scores of ≥25 and ≥15 significantly reduced the odds against A/H1N1 (0.10; p=0.01) and non-group 1 (0.06; p=0.0004) influenza virus infections, respectively. These ADCD scores were associated with >84% likelihood of risk reduction. H1 stalk-specific ADCC potential was not associated with protection against influenza-illness. CONCLUSION: H1 stalk-specific ADCD correlates with protection against influenza-illness following influenza vaccination during pregnancy. These findings provide insight into the protective mechanisms of HA stalk antibodies.

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.

Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation.

SARS-CoV-2 clearance requires adaptive immunity but the contribution of neutralizing antibodies and T cells in different immune states is unclear. Here we ask which adaptive immune responses associate with clearance of long-term SARS-CoV-2 infection in HIV-mediated immunosuppression after suppressive antiretroviral therapy (ART) initiation. We assembled a cohort of SARS-CoV-2 infected people in South Africa (n = 994) including participants with advanced HIV disease characterized by immunosuppression due to T cell depletion. Fifty-four percent of participants with advanced HIV disease had prolonged SARS-CoV-2 infection (>1 month). In the five vaccinated participants with advanced HIV disease tested, SARS-CoV-2 clearance associates with emergence of neutralizing antibodies but not SARS-CoV-2 specific CD8 T cells, while CD4 T cell responses were not determined due to low cell numbers. Further, complete HIV suppression is not required for clearance, although it is necessary for an effective vaccine response. Persistent SARS-CoV-2 infection led to SARS-CoV-2 evolution, including virus with extensive neutralization escape in a Delta variant infected participant. The results provide evidence that neutralizing antibodies are required for SARS-CoV-2 clearance in HIV-mediated immunosuppression recovery, and that suppressive ART is necessary to curtail evolution of co-infecting pathogens to reduce individual health consequences as well as public health risk linked with generation of escape mutants.

Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity.

SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.

Protective efficacy of a plant-produced beta variant rSARS-CoV-2 VLP vaccine in golden Syrian hamsters.

In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats.

Vaccinating people living with HIV: a fast track to preventive and therapeutic HIV vaccines.

Globally, the number of new HIV infections remains unacceptably high, and urgent new approaches are needed to advance HIV vaccine science. However, the development of a preventive HIV vaccine has proven to be an intractable scientific challenge. Recent advances in HIV immunogen design have taken the field a step closer to triggering the rare precursors of broadly neutralising antibodies, which are widely assumed to be necessary for a vaccine. Nonetheless, these same studies and previous studies in people living with HIV have also highlighted the major hurdles that must be overcome to boost the cross-reactivity and potency of these responses to sufficient levels. Here, we describe an opportunity for fast-tracking the evaluation of candidate preventive and therapeutic vaccines by immunising people with HIV who are antiretroviral therapy suppressed. We argue that such studies, unlike traditional studies of vaccines in participants not infected with HIV, will be faster and more informative and will allow the vaccine field to bypass multiple hurdles. This approach will accelerate the process of defining the capacity of immunogens to trigger relevant antibodies, currently an extremely slow and expensive pathway, and provide a quick path to creating an HIV vaccine.

Development of LIBRA-seq for the guinea pig model system as a tool for the evaluation of antibody responses to multivalent HIV-1 vaccines.

Consistent elicitation of serum antibody responses that neutralize diverse clades of HIV-1 remains a primary goal of HIV-1 vaccine research. Prior work has defined key features of soluble HIV-1 Envelope (Env) immunogen cocktails that influence the neutralization breadth and potency of multivalent vaccine-elicited antibody responses including the number of Env strains in the regimen. We designed immunization groups that consisted of different numbers of SOSIP Env strains to be used in a cocktail immunization strategy: the smallest cocktail (group 2) consisted of a set of two Env strains, which were a subset of the three Env strains that made up group 3, which, in turn, were a subset of the six Env strains that made up group 4. Serum neutralizing titers were modestly broader in guinea pigs that were immunized with a cocktail of three Envs compared to cocktails of two and six, suggesting that multivalent Env immunization could provide a benefit but may be detrimental when the cocktail size is too large. We then adapted the LIBRA-seq platform for antibody discovery to be compatible with guinea pigs, and isolated several tier 2 neutralizing monoclonal antibodies. Three antibodies isolated from two separate guinea pigs were similar in their gene usage and CDR3s, establishing evidence for a guinea pig public clonotype elicited through vaccination. Taken together, this work investigated multivalent HIV-1 Env immunization strategies and provides a novel methodology for screening guinea pig B cell receptor antigen specificity at a high-throughput level using LIBRA-seq.IMPORTANCEMultivalent vaccination with soluble Env immunogens is at the forefront of HIV-1 vaccination strategies but little is known about the influence of the number of Env strains included in vaccine cocktails. Our results suggest that adding more strains is sometimes beneficial but may be detrimental when the number of strains is too high. In addition, we adapted the LIBRA-seq platform to be compatible with guinea pig samples and isolated several tier 2 neutralizing monoclonal antibodies, some of which share V and J gene usage and >70% CDR3 identity, thus establishing the existence of public clonotypes in guinea pigs elicited through vaccination.

Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.

Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection.

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.

Seroprevalence survey of anti-SARS-CoV-2 antibody and associated factors in South Africa: Findings of the 2020-2021 population-based household survey.

Population-based serological testing is important to understand the epidemiology and estimate the true cumulative incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to inform public health interventions. This study reports findings of a national household population SARS-CoV-2 serosurvey in people 12 years and older in South Africa. This cross-sectional multi-stage random stratified cluster survey undertaken from November 2020 to June 2021 collected sociodemographic data, medical history, behavioural data, and blood samples from consenting participants. The samples were tested for SARS-CoV-2 antibodies using the Roche ElecsysAnti-SARS-CoV-2 chemiluminescence immunoassay (CLIA) Total Antibody Test. The survey data were weighted by age, race, sex, and province with final individual weights benchmarked against the 2020 mid-year population estimates and accounted for clustering. Descriptive statistics summarize the characteristics of participants and seroprevalence. Logistic regression analyses were used to identify factors associated with seropositivity. From 13290 survey participants (median age 33 years, interquartile range (IQR) 23-46 years), SARS-CoV-2 seroprevalence was 37.8% [95% Confidence Interval (CI) 35.4-40.4] and varied substantially across the country's nine provinces, and by sex, age and locality type. In the final adjusted model, the odds of seropositivity were higher in women than in men [aOR = 1.3 (95% CI: 1.0-1.6), p = 0.027], and those living with HIV (self-report) [aOR = 1.6 (95% CI: 1.0-2.4), p = 0.031]. The odds were lower among those 50 years and older compared to adolescents 12-19 years old [aOR = 0.6 (95% CI: 0.5-0.8), p<0.001] and in those who did not attend events or gatherings [aOR = 0.7 (95% CI: 0.6-1.0), p = 0.020]. The findings help us understand the epidemiology of SARS-CoV-2 within different regions in a low-middle-income country. The survey highlights the higher risk of infection in women in South Africa likely driven by their home and workplace roles and also highlighted a need to actively target and include younger people in the COVID-19 response.

Anticipating HIV viral escape - resistance to active and passive immunization.

PURPOSE: Active and passive immunization strategies are challenged by the extraordinary diversity of HIV, and the need for high titers of neutralizing antibodies to confer protective immunity. This review summarises recent studies and the barrier that these interventions will need to overcome to prevent viral resistance. RECENT FINDINGS: Studies from the antibody mediated prevention trial identified a measure of protective titers, finding that higher titers than anticipated will be needed to prevent infection. This benchmark has advanced our ability to predict combinations of broadly neutralizing antibodies (bNAbs) that will provide optimal coverage. To limit escape, these combinations should ensure that the majority of viruses are bound by a minimum of two antibodies. The characterization of currently circulating viruses has revealed increased resistance to some bNAbs over time, highlighting the need for continued surveillance, especially in under-studied populations and subtypes. Active vaccination will face similar challenges in combating diversity, although despite successes in germline targeting, this approach is not yet able to elicit bNAbs. SUMMARY: Cumulatively these studies highlight the need to target multiple antibody epitopes for maximum coverage, but also to restrict escape pathways. Successful immunization strategies should anticipate viral escape and devise strategies to counteract this.

Despite delayed kinetics, people living with HIV achieve equivalent antibody function after SARS-CoV-2 infection or vaccination.

The kinetics of Fc-mediated functions following SARS-CoV-2 infection or vaccination in people living with HIV (PLWH) are not known. We compared SARS-CoV-2 spike-specific Fc functions, binding, and neutralization in PLWH and people without HIV (PWOH) during acute infection (without prior vaccination) with either the D614G or Beta variants of SARS-CoV-2, or vaccination with ChAdOx1 nCoV-19. Antiretroviral treatment (ART)-naïve PLWH had significantly lower levels of IgG binding, neutralization, and antibody-dependent cellular phagocytosis (ADCP) compared with PLWH on ART. The magnitude of antibody-dependent cellular cytotoxicity (ADCC), complement deposition (ADCD), and cellular trogocytosis (ADCT) was differentially triggered by D614G and Beta. The kinetics of spike IgG-binding antibodies, ADCC, and ADCD were similar, irrespective of the infecting variant between PWOH and PLWH overall. However, compared with PWOH, PLWH infected with D614G had delayed neutralization and ADCP. Furthermore, Beta infection resulted in delayed ADCT, regardless of HIV status. Despite these delays, we observed improved coordination between binding and neutralizing responses and Fc functions in PLWH. In contrast to D614G infection, binding responses in PLWH following ChAdOx-1 nCoV-19 vaccination were delayed, while neutralization and ADCP had similar timing of onset, but lower magnitude, and ADCC was significantly higher than in PWOH. Overall, despite delayed and differential kinetics, PLWH on ART develop comparable responses to PWOH, supporting the prioritization of ART rollout and SARS-CoV-2 vaccination in PLWH.