Biology subjects

Alexandre, M.

Publications and source records attributed to Alexandre, M..

3 recordsLinked to original sources

bioRxiv2026

Joint mechanistic modeling of viral and antibody responses to vaccines in non-human primates to quantify SARS-CoV-2 mechanistic correlates of protection

In a global SARS-CoV-2 landscape of hybrid immunity resulting from a vaccinated worldwide population and the emergence of new variants able to escape immunity, the identification and quantification of correlates of protection (CoPs) is crucial for the adaptation of next-generation SARS-CoV-2 vaccines. Antibodies and their neutralizing capacity have been identified as reliable mechanistic CoPs. Here, we proposed an original mechanistic model jointly describing viral and antibody dynamics, and their mutual interactions, observed after SARS-CoV-2 infection in non-human primates (NHPs) with distinct immunological backgrounds. From the model, the concentration of neutralizing antibodies being protective against viral infection spreading was derived using the reproduction number. Counterfactual simulations were also performed to better understand and validate immune mechanisms driving immune control. The model was estimated on viral, binding (bAb), and neutralizing (nAb) antibody dynamics, with data collected in 34 naive and convalescent NHPs. Animals were involved in a preclinical study evaluating two next-generation protein-based vaccines targeting the RBD of the Spike protein to CD40-expressing cells, and the original BNT162b2 mRNA vaccine against Delta SARS-CoV-2 infection. Our model validated the functionality of nAb to neutralize viruses as the primary mechanism of protection. An inhibitory antibody concentration against Delta variant of 20 AU/mL was deemed protective against Delta infection in naive animals. Moreover, we showed the strong benefit of hybrid immunity to induce faster and more protective antibody responses pointing out the crucial role of the memory B-cell immune response in viral control. Finally, an additional effect of natural immunity beyond antibodies and enhancing the elimination of infected cells was identified, suggesting the potential role of the T-cell response in viral control. Our model showed the benefit of combining information from both viral and antibody responses to better qualitatively and quantitatively inform on their protective capacity against Delta SARS-CoV-2 infection.

immunology↗

bioRxiv2022

Impact of variants of concern on SARS-CoV-2 viral dynamics in non-human primates.

The impact of variants of concern (VoC) on SARS-CoV-2 viral dynamics remains poorly understood and essentially relies on observational studies subject to various sorts of biases. In contrast, experimental models of infection constitute a powerful model to perform controlled comparisons of the viral dynamics observed with VoC and better quantify how VoC escape from the immune response. Here we used molecular and infectious viral load of 78 cynomolgus macaques to characterize in detail the effects of VoC on viral dynamics. We first developed a mathematical model that recapitulate the observed dynamics, and we found that the best model describing the data assumed a rapid antigen-dependent stimulation of the immune response leading to a rapid reduction of viral infectivity. When compared with the historical variant, all VoC except beta were associated with an escape from this immune response, and this effect was particularly sensitive for delta and omicron variant (p<10-6 for both). Interestingly, delta variant was associated with a 1.8-fold increased viral production rate (p=0.046), while conversely omicron variant was associated with a 14-fold reduction in viral production rate (p<10-6). During a natural infection, our models predict that delta variant is associated with a higher peak viral RNA than omicron variant (7.6 log10 copies/mL 95% CI 6.8 - 8 for delta; 5.6 log10 copies/mL 95% CI 4.8 - 6.3 for omicron) while having similar peak infectious titers (3.7 log10 PFU/mL 95% CI 2.4 - 4.6 for delta; 2.8 log10 PFU/mL 95% CI 1.9 - 3.8 for omicron). These results provide a detailed picture of the effects of VoC on total and infectious viral load and may help understand some differences observed in the patterns of viral transmission of these viruses.

microbiology↗

bioRxiv2021

SARS-CoV-2 mechanistic correlates of protection: insight from modelling response to vaccines

The definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication. One Sentence SummaryA framework for modelling the immune control of viral dynamics is applied to quantify the effect of several SARS-CoV-2 vaccine platforms and to define mechanistic correlates of protection.

immunology↗