Inhibition of respiratory pathogens Mycobacterium tuberculosis and SARS-CoV-2 by human serum and monoclonal antibodies

Antibodies are a key host immune response against pathogens. Yet the effects of antibodies on Mycobacterium tuberculosis (Mtb) at the cellular level are incompletely understood, as is the effect of HIV co-infection on antibody-mediated immunity to SARS-CoV-2. By investigating these questions at the epicenter of the HIV/TB co-epidemic in KwaZulu-Natal, South Africa, I have: 1) Cloned immunoglobulins from B cells of Mtb-exposed donors and investigated the effect of Mtb-specific polyclonal and monoclonal antibodies on infection of macrophages; 2) Characterised antibody responses in viraemic, virologically suppressed, and HIV-negative Covid-19 patients to determine whether HIV status and viraemia influence neutralization of SARS-CoV-2. Sera from TB-exposed individuals on average increased host cell survival and inhibited intracellular bacterial growth compared to non-specific control serum, although there was a wide range of individual variation. I cloned several Mtb-specific antibodies from South African donors including one which significantly inhibited intracellular bacterial growth in THP-1 monocytes and primary macrophages. I developed a live virus neutralisation assay for SARS-CoV-2 to circumvent the problem of a lentiviral pseudovirus neutralization assay being incompatible with samples containing antiretrovirals for HIV. Among Covid-19 patients, the kinetics of RBD-binding and neutralising antibodies differed little between HIV-uninfected and virologically suppressed people living with HIV (PLWH), whereas viraemic PLWH had a much lower and delayed response. In addition, I observed that plasma from individuals either previously infected with earlier variants of SARS-CoV-2 or vaccinated with AstraZeneca’s AZD1222 recombinant adenovirus vaccine showed decreases in neutralisation against newer variants of concern. Taken together, these results demonstrate that antibody-mediated immunity is relevant to the control of TB but is highly heterogeneous. Similarly, there is individual heterogeneity in the neutralisation response to SARS-CoV-2, with the latter partially determined by HIV status and suppression state