Biology subjects

Gonelli, C. A.

Publications and source records attributed to Gonelli, C. A..

3 recordsLinked to original sources

bioRxiv2026

Novel monoclonal antibodies targeting distinct sites on placental binding P. falciparum antigen VAR2CSA synergistically enhance parasite phagocytosis

Placental malaria, due to the sequestration of Plasmodium falciparum-infected erythrocytes (IE), causes adverse pregnancy outcomes. The sequestration is mediated by VAR2CSA, a protein that binds to placental chondroitin sulfate A (CSA). VAR2CSA antibodies protect against adverse pregnancy outcomes; however, no licensed VAR2CSA-based vaccine or therapeutic exists to date. We identified and expressed VAR2CSA-specific IgG1 monoclonal antibodies (mAbs) using B cells of malaria-exposed Papua New Guinean women. VAR2CSA mAbs were characterised by their ability to recognise eight heterologous CSA-binding P. falciparum strains, to neutralise CSA binding and/or to induce phagocytosis of IEs by THP-1 monocytes. We identified 16 mAbs, all of which targeted just two of the six domains of VAR2CSA, DBL3X and DBL5{varepsilon}. Cross-reactivity varied between mAbs, but was highest among mAbs to DBL5{varepsilon}, with four of eight of these mAbs binding to all eight strains. Although individual mAbs did not promote phagocytosis, combinations of mAbs recognising distinct epitopes either on the same domain or over different domains did. None of the mAbs inhibited IEs from binding to CSA. Our findings suggest that a combination of mAbs recognising more than one epitope would be needed for a therapeutic aiming to promote parasite clearance by phagocytosis; that DBL5{varepsilon} could be considered for a VAR2CSA vaccine that aims to elicit cross-reactive antibodies that promote phagocytosis; and that identification of binding-inhibitory mAbs requires thoughtful B-cell bait design.

microbiology↗

bioRxiv2025

Immunodominance is a poor predictor of vaccine-induced T follicular helper cell quality

Rational engineering of vaccine immunogens to focus B cell responses on potently neutralizing epitopes is a promising approach to improve the potency, breadth and durability of viral vaccines. Such strategies, however, can compromise vaccine immunogenicity through the unintended exclusion of CD4+ T cell epitopes, which are critical for the development of T follicular helper (TFH) cells and to support high affinity antibody production. Using a prototypic influenza HA stem immunogen lacking effective CD4+ T cell help in BL6 mice, we interrogated the minimal requirements for T cell help needed to drive serological responses to vaccination. We find that priming of naive CD4 T cells is markedly efficient, however the immunodominance of a given CD4 T cell epitope is not predictive of the propensity to provide high quality help to antigen-specific B cells. In the context of soluble antigens, provision of a single MHC class II epitope is sufficient to drive robust germinal centre responses and serum IgG titres. However not all CD4 epitopes provide equivalent levels of B cell help, despite priming comparable numbers of antigen-specific CD4 T cells. Finally, we show multimerizing and arraying antigens on nanoparticle scaffolds unlocks highly subdominant, near-undetectable CD4 T cell helper responses to support a T-dependent antibody response. Our findings emphasize the importance of CD4+ T cell help for programing robust and durable humoral immunity, and provide crucial insights to guide the rational incorporation of favorable T cell epitopes into vaccines.

immunology↗

bioRxiv2025

Memory T and B cells with recognition of avian influenza hemagglutinins are poorly responsive to existing seasonal influenza vaccines

Immunisation remains the most cost-effective mechanism to combat global influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population level immunity, which could translate into an influenza pandemic. Therefore, there is a need to better understand pre-existing human immunity against avian influenza strains. as highlighted by the recent rapid, global spread of avian H5Nx clade 2.3.4.4b variants. Here, we sought to quantify the frequencies and specificities of B cells recognising avian hemagglutinin (HA) within unexposed adults, and to characterise the ability of seasonal immunisation to boost cross-reactive immune responses to H5Nx strains, including from clade 2.3.4.4b. Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross-reactive recognition of H5 and H7 HA was low and 2-5 fold lower than populations of seasonal H1N1 and H3N2 HA-specific B cells. Boosting of B cell responses against H5Nx clade 2.3.4.4b HA following seasonal immunisation were sporadic with only 3 out of 19 individuals showing an increased population of probe-positive cells. Cross-reactive B cells generally expressed immunoglobulins drawn from variable heavy chain genes associated with recognition of the HA stem (VH6-1, VH1-69, VH1-18). CD4+ T cell responses towards H5 HA were also weakly boosted with little to no increase in circulating T follicular helper cell populations. These findings highlight the need for avian influenza-specific vaccine products to bolster immunity in human populations, with consideration for use in pre-pandemic preparedness to expand baseline frequencies of avian influenza-specific memory B and T lymphocytes.

immunology↗