BRAIN AND BEHAVIOR PREDICTORS OF SARS-CoV-2 INFECTION AMONG PEOPLE WITH HIV

Background: Recent findings from the UK Biobank revealed that healthy adults who later became infected with SARS-CoV-2 had lower brain volumes in regions involved in risk-taking behavior and olfaction compared to individuals who did not become infected. We examined if similar pre-existing differences in brain regions correspond to SARS-CoV-2 infection among people with HIV (PWH) receiving suppressive ART. Method(s): Participants included adult Thai MSM enrolled in the acute HIV (AHI) cohort (RV254/SEARCH010) in Bangkok, Thailand. Participants underwent 3T MRI and clinical assessments (i.e., HIV disease metrics, cognitive testing, and self-reported mood and substance use). ART initiation occurred within 5 days of the MRI (median=same day). Regional brain volumes were summed across hemispheres and corrected for head size. Brain volumes and clinical indices were compared between participants with laboratory confirmed SARS-CoV-2 and those without a diagnosis of SARS-CoV-2 following ART initiation. Machine learning was utilized to identify variables at the time of enrollment into the cohort that predicted subsequent SARS-CoV-2 infection status. Result(s): 112 participants were included in the analysis. All study participants achieved viral suppression after ART and received SARS-CoV-2 vaccinations. Fifty-four participants became infected with SARS-CoV-2 during the observation period (median=79 weeks from ART initiation). Study participants who became infected with SARS-CoV-2 after ART had lower volumes at the time of enrollment in several subcortical brain regions with the most pronounced effect in the pallidum (p=.025). There were no associations between brain volumes and ratings of mood, demographics, or HIV disease indices. SARS-CoV-2 infection was two-fold higher among individuals who reported use of amyl nitrites (i.e., poppers) during chemsex. Machine learning with repeated cross validation revealed that lower orbital and medial frontal lobe, anterior cingulate, pallidum, vermis, and olfactory volumes, worse motor function, and higher education collectively predicted co-infection status (average AUC of 85%). Conclusion(s): Study findings point toward a risk phenotype for SARS-CoV-2 infection among PWH defined by pre-existing differences in brain volumes relevant to risk-taking behavior, emotion, and neuroHIV as well as behavioral factors such as inhalant use and lack of social distancing during chemsex. (Table Presented).

Longitudinal Coronavirus Antibody Responses in Africa between 2013 and 2021

Background: Pre-existing coronavirus-specific antibody responses may affect SARS-CoV-2 responses. We evaluated longitudinal samples obtained before and during the pandemic in participants from Kenya, Nigeria, Tanzania and Uganda;90% were people living with HIV. Method(s): Serum samples were tested using a multiplex bead-based immunoassay to measure antibody binding against 22 antigens including Nucleocapsid (N) and Spike (S) proteins of the 7 human coronaviruses and one malaria antigen. Result(s): We tested 819 longitudinal samples from 80 participants collected between July 2013 and May 2021 (3-16 samples per participant). Using a signal to noise ratio (S/N) >10, 13, 1, and 5 participants showed at least one time point with IgG responses to S of SARS-CoV-2 (ancestral), SARS-CoV-1 and MERS-CoV respectively while 14, 8, and 11 participants showed responses to N before 2020. Across individuals, IgG binding to SARS-CoV-2 S subunit S2 was most frequently detected and it showed the highest within-host fluctuations over time. A few individuals had elevated responses that persisted over years towards multiple antigens, most frequently to different SARS-CoV-2 antigens and rarely to distinct viruses. One individual showed high RBD-specific IgG responses to distinct coronaviruses at a single time point before 2020. Responses against coronaviruses measured post-2020 generally correlated with responses measured before 2020, except for a subset of infected individuals whose responses against SARS-CoV-2 dramatically increased post-pandemic. IgG responses against the ancestral SARS-CoV-2 variant were most correlated with responses against Alpha and Gamma (then to Beta and Delta, rho >0.75) variants. Using an IgM S/N >10, 31 participants were Malaria positive and 22 showed concurrent elevated coronavirus IgM responses. However, about half of the malaria positive participants had no IgG responses against any coronavirus antigen and the rest presented limited and variable patterns of association between responses against coronaviruses and malaria. Conclusion(s): Our study confirmed that a small subset of individuals in Africa had long-lasting IgG coronavirus-specific antibodies before the pandemic. While there was an association between coronavirus IgM responses and responses against malaria, there was no correlation between IgG responses and malaria infection. Further analysis is needed to better understand the interactions between antigens in the development of antibody immunity to coronaviruses. (Table Presented).

HIGHER CORONAVIRUS ANTIBODY RESPONSES PREPANDEMIC in AFRICA THAN in THAILAND

Background: COVID-19 clinical manifestations range from asymptomatic to severe disease. Prior immune responses to human coronaviruses may affect individual responses to SARS-CoV-2. We surveyed coronavirus responses pre-pandemic in individuals from Kenya, Nigeria, Tanzania, Uganda and Thailand;81% were people living with HIV. Methods: Specimens were screened for SARS-CoV-2 Spike S2 subunit IgG responses. Selected samples were tested using a bead-based immunoassay that profiled the specificity, isotype and subclass of antibody responses to coronavirus, flavivirus and HIV antigens. Wilcoxon rank sum tests were performed to compare responses across antigens and participant group. Results: We screened 1,875 samples (one per individual) collected between 2013 and October 2019: 1,630 samples were from Africa (87%) and 245 from Thailand. 6.99% of participants (n=131, 116 from Africa (89%) and 15 from Thailand) showed responses above the naïve signal threshold and were further tested. Using a signal to noise ratio of >10 as a cut-off value, 44, 27 and 42 samples showed IgG responses to the Spike protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV respectively, while 7, 9 and 4 samples showed responses to Nucleocapsid for these same antigens. Some individuals had higher responses than those seen in SARS-CoV-2 convalescent individuals. We found a strikingly different pattern of reactivity in Africa compared to Thailand (Figure 1). Antibody responses were significantly higher in the African participants compared to Thai participants across antigens corresponding to SARS-CoV-2 (p<0.001), SARS-CoV-1 (p<0.001) and MERS-CoV (p<0.01). Similar patterns were seen for IgG subclasses, IgA and IgM. The difference was less pronounced for the four endemic coronaviruses, nonetheless anti-Spike responses were significantly higher in African participants for HKU1 and OC43 (p≤0.018). In addition, mapping responses to 21 flavivirus antigens showed the highest reactivity in Thailand and in Nigeria. Conclusion: Our serosurvey of pre-pandemic samples showed that there were significantly higher antibody responses against coronaviruses, including SARS-CoV-2, in Africa than in Thailand. Profiling flavivirus responses showed that the difference between the two regions was not due to a higher background reactivity across African samples. Further analysis is needed to explain pre-pandemic SARS-CoV-2-like antibody responses among African participants and explore implications for geographic diversity in disease severity.

A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates

[Figure: see text].

Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein.

The 'D614G' mutation (Aspartate-to-Glycine change at position 614) of the SARS-CoV-2 spike protein has been speculated to adversely affect the efficacy of most vaccines and countermeasures that target this glycoprotein, necessitating frequent vaccine matching. Virus neutralisation assays were performed using sera from ferrets which received two doses of the INO-4800 COVID-19 vaccine, and Australian virus isolates (VIC01, SA01 and VIC31) which either possess or lack this mutation but are otherwise comparable. Through this approach, supported by biomolecular modelling of this mutation and the commonly-associated P314L mutation in the RNA-dependent RNA polymerase, we have shown that there is no experimental evidence to support this speculation. We additionally demonstrate that the putative elastase cleavage site introduced by the D614G mutation is unlikely to be accessible to proteases.

ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets.

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.