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SARS-CoV-2 Omicron (B.1.1.529) BA.4 and BA.5 sub-lineages, first detected in South Africa, have changes relative to Omicron BA.1 including substitutions in the spike receptor binding domain. Here we isolated live BA.4 and BA.5 viruses and measured BA.4/BA.5 neutralization elicited by BA.1 infection either in the absence or presence of previous vaccination as well as from vaccination without BA.1 infection. In BA.1-infected unvaccinated individuals, neutralization relative to BA.1 declines 7.6-fold for BA.4 and 7.5-fold for BA.5. In vaccinated individuals with subsequent BA.1 infection, neutralization relative to BA.1 decreases 3.2-fold for BA.4 and 2.6-fold for BA.5. The fold-drop versus ancestral virus neutralization in this group is 4.0-fold for BA.1, 12.9-fold for BA.4, and 10.3-fold for BA.5. In contrast, BA.4/BA.5 escape is similar to BA.1 in the absence of BA.1 elicited immunity: fold-drop relative to ancestral virus neutralization is 19.8-fold for BA.1, 19.6-fold for BA.4, and 20.9-fold for BA.5. These results show considerable escape of BA.4/BA.5 from BA.1 elicited immunity which is moderated with vaccination and may indicate that BA.4/BA.5 may have the strongest selective advantage in evading neutralization relative to BA.1 in unvaccinated, BA.1 infected individuals. Emerging SARS-CoV-2 Omicron sub-lineages BA.4 and BA.5 raise concerns about potential immune evasion. Here, Khan et al. show that both BA.4 and BA.5 are able to escape immune response induced by prior BA.1 infection, but that this effect is less pronounced in vaccinated individuals.

Omicron BA.2.86 subvariant differs from Omicron BA.2 as well as recently circulating variants by over 30 mutations in the spike protein alone. Here we report on the isolation of the live BA.2.86 subvariant from a diagnostic swab collected in South Africa which we tested for escape from neutralizing antibodies and viral replication properties in cell culture. We found that BA.2.86 does not have significantly more escape relative to Omicron XBB.1.5 from neutralizing immunity elicited by either Omicron XBB-family subvariant infection or from residual neutralizing immunity of recently collected sera from the South African population. BA.2.86 does have extensive escape relative to ancestral virus with the D614G substitution (B.1 lineage) when neutralized by sera from pre-Omicron vaccinated individuals and relative to Omicron BA.1 when neutralized by sera from Omicron BA.1 infected individuals. BA.2.86 and XBB.1.5 show similar viral infection dynamics in the VeroE6-TMPRSS2 and H1299-ACE2 cell lines. We also investigate the relationship of BA.2.86 to BA.2 sequences. The closest BA.2 sequences are BA.2 samples from Southern Africa circulating in early 2022. Similarly, many basal BA.2.86 sequences were sampled in Southern Africa. This suggests that BA.2.86 potentially evolved in this region, and that unobserved evolution led to escape from neutralizing antibodies similar in scale to recently circulating strains of SARS-CoV-2. The Omicron BA.2.86 subvariant differs from previous variants by over 30 spike mutations. Here, the authors report that BA.2.86 likely evolved in Southern Africa and that its immune escape is not larger than recently circulating SARS-CoV-2 strains. Neither its replication nor its pathogenicity are enhanced in vitro.

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. There is limited data on immune factors contributing to SARS-CoV-2 viral clearance in people living with HIV. Here, the authors show that re-emergence of the neutralizing antibody response may be key to clearing persistent SARS-CoV-2 infection in ART-mediated recovery from immunosuppression in advanced HIV disease.

Background Severe Covid-19 leads to higher neutralizing antibody levels, a key correlate of protection. However, the host proteins associated with this response have not been fully characterized. We asked which proteins in the blood plasma associate with neutralization, anti-spike antibody levels, and disease severity in a South African cohort upon first SARS-CoV-2 exposure. Methods We used a longitudinal observational cohort design to collect blood at 6 days (acute infection) and 32 days (convalescence) post-diagnosis. We performed SomaScan proteomics on acute blood plasma and measured SARS-CoV-2 plasma neutralization capacity and anti-spike antibody levels in convalescent plasma. Disease severity was scored based on requirement for supplemental oxygen and was mild to moderate (no critically ill participants). Results We find differentially expressed proteins associating with neutralization, anti-spike antibody levels, and disease severity, with strong overlap between proteins associated with neutralization and spike binding, and moderate overlap between neutralization and disease severity. High neutralizers, regardless of requirement for supplemental oxygen, are found to have risk factors and markers for being more ill compared to low neutralizers. We can reasonably predict who becomes a high neutralizer based on individual proteins. The best predictor for neutralization is HSPA8, known to bind viral proteins and cross-present extracellular antigens. The strongest associated pathway is fatty acid metabolism, whose inhibition results in suppression of viral replication. Conclusions These results show that host proteins and pathways involved early in SARS-CoV-2 infection associate with neutralizing antibody levels elicited by the infection at convalescence. Plain Language Summary The immune response to SARS-CoV-2 infection leads to the production of antibodies that prevent the virus from infecting cells. This protects people from future infections with the same virus. People differ in their ability to make antibody responses after infection. The source of this variability, in terms of differences in expressed proteins, remains poorly understood. Here, we categorize South African study participants who were infected with SARS-CoV-2 for the first time into those with high and low antibody responses and link this with differences in specific proteins close to the time of infection. We find that proteins and pathways which play a role in SARS-CoV-2 infection also associate with stronger antibody responses. Khairallah et al., investigate the host proteins associated with a strong neutralizing antibody response to SARS-CoV-2. High neutralizing antibody responses to SARS-CoV-2 are associated with specific protein expression patterns, especially HSPA8 and pathways like fatty acid metabolism, which can predict immune strength and correlate with disease severity.

The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections 1 . Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches. Plasma from individuals vaccinated with BNT162b2 exhibits 22-fold less neutralization capacity against Omicron (B.1.1.529) than against an ancestral SARS-CoV-2 strain but residual neutralization is maintained in those with high levels of neutralization of ancestral virus.

The extent to which Omicron infection 1 – 9 , with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3–9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19–27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement. A study quantifying the neutralization of severe acute respiratory syndrome coronavirus 2 variants in individuals infected with Omicron/BA.1 shows that vaccinated individuals previously infected with Omicron have enhanced protection against reinfection with current variants, \\including Omicron/BA.2, while Omicron/BA.1 infected unvaccinated individuals have limited protection.

Abstract One mechanism of variant formation may be evolution during long-term infection in immunosuppressed people. To understand the viral phenotypes evolved during such infection, we tested SARS-CoV-2 viruses evolved from an ancestral B.1 lineage infection lasting over 190 days post-diagnosis in an advanced HIV disease immunosuppressed individual. Sequence and phylogenetic analysis showed two evolving sub-lineages, with the second sub-lineage replacing the first sub-lineage in a seeming evolutionary sweep. Each sub-lineage independently evolved escape from neutralizing antibodies. The most evolved virus for the first sub-lineage (isolated day 34) and the second sub-lineage (isolated day 190) showed similar escape from ancestral SARS-CoV-2 and Delta-variant infection elicited neutralizing immunity despite having no spike mutations in common relative to the B.1 lineage. The day 190 isolate also evolved higher cell-cell fusion and faster viral replication and caused more cell death relative to virus isolated soon after diagnosis, though cell death was similar to day 34 first sub-lineage virus. These data show that SARS-CoV-2 strains in prolonged infection in a single individual can follow independent evolutionary trajectories which lead to neutralization escape and other changes in viral properties.

BackgroundOur study aimed to determine the neutralizing capacity of anti-SARS-CoV-2 antibodies found in the plasma of pregnant women collected during the pre-pandemic period to COVID-19 in three settlements in Cameroon.MethodsA total of 1,590 archival plasma from pregnant women during pregnancy (574) and at delivery (657) were tested for COVID-19 using the Abbott Panbio TM COVID-19 IgG/IgM rapid diagnostic test. Samples from 120 (9.75%) women were collected from the rural area, 663 (53.86%) in the peri-urban area, and 448 (36.40%) in an urban area at different antenatal visits. To ascertain our findings, randomly selected IgG & IgG/M positive samples (70) were further tested by the Luminex technology specific for viral N and S proteins. The neutralizing capacity of 21 samples with the highest titers against the S protein were assessed against the founder SAR CoV-2. Data was summarized in proportions.ResultsDuring pregnancy with the Luminex technology, 12.50% (4/32) and 3.13% (1/32) of pregnant women were seropositive to the S-protein and N/S proteins respectively. At delivery, 50% (10/20) of women were seropositive for anti-coronaviruses IgG directed against the S-protein only and 15% (3/20) while had antibodies against the N&S protein. A transplacental transfer of protective S proteins from the mother to the child was found in 60% (3/5) of the tested dyads. During the neutralization assay, 0% of these antibodies found in these pregnant women before the pre-pandemic period at COVID-19 were neutralizing to the ancestral strain.ConclusionThis study provides evidence of existing of cross-reactive anti-SARS-CoV-2 antibodies among pregnant Cameroonian women in the Pre-COVID-19 eras but are not neutralizing against the ancestral virus.Funding source: ANRS