CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: PWH on ART receiving a bivalent booster as fourth dose were enrolled. We measured immune responses against WT and BA.4-5 virus: RBD-binding Abs (ELISA); RBD-blocking Abs (RBD-ACE2 binding inhibition assay); Th1/Tc1 cytokine (IFN-γ/TNF-α/IL-2)-producing and cytotoxic (CD107a+) CD4/CD8 T-cells (flow cytometry after PBMCs stimulation with spike peptides) before (T0) and 1 month after (T1) the 4th dose. Wilcoxon test was used for statistical analyses. Results: We included 30 PWH who received the 4th dose at a median time of 14.5 (IQR: 13.5–15) months after the 3rd one. Median CD4 T-cell count was 790/μL (IQR: 598–929) and HIV-RNA <20 copies/mL. Demographic and viro immunologic features are reported in Fig.1A. The 4th dose led to an increase of RBD-binding/blocking Abs against both WT and BA.4-5. Interestingly, when compared to WT, BA.4-5–specific humoral immunity was lower at both T0 and T1. Frequencies of Th1/Tc1 and cytotoxic CD4/CD8 T-cells against WT and BA.4-5 did not increase after the booster, with similar values of WT– and BA.4-5–specific responses both before and after the booster administration (Fig.1D–G). Despite stable frequencies, polyfunctionality of WT/BA.4-5–specific T-cells was increased after the booster, and yet the proportion of BA.4-5– specific polyfunctional IFN-γ+TNF-α+IL-2+/IFN-γ+TNF-α+IL-2– CD4 T-cells and IFN- γ+TNF-α+IL-2– CD8 T-cells were lower than WT–specific ones at all time-points. Conclusion: In PWH on effective ART, an original/BA.4-5 bivalent booster increases RBD-binding/blocking Abs and T-cell polyfunctionality against both WT and BA.4-5. However, humoral and polyfunctional T-cell responses hold higher against WT than BA.4-5 both before and after the booster, suggesting immune imprinting to the wild-type strain. By showing a strengthened antigen-specific immune response, our data reinforce the importance of a variant-adapted mRNA boosters in PWH, possibly directed against the dominant Immune Response to SARS-CoV-2 Omicron Breakthrough is a Recall of Vaccine-Induced Memory Jernej Pusnik 1 , Jasmin Zorn 1 , Werner O. Monzon Posadas 1 , Kathrin Peters 1 , Emmanuil Osypchuk 1 , Sabine Blaschke 2 , Hendrik Streeck 1 1 Bonn University Hospital, Bonn, Germany, 2 University Medical Center Göttingen, Göttingen, Germany Background: The COVID-19 vaccination campaign is considered the largest in history with over 70% of the global population having received at least one vaccine dose. While vaccination demonstrated outstanding results in cutting down the severity of the disease, breakthrough infections with the Omicron derived variants occur frequently. Others and we have previously shown that vaccinated individuals develop a potent B cell response following the Omicron breakthrough infection. It is however not clear whether this is due to the reactivation of vaccine-induced memory or de novo response specific for the mutated regions of the spike protein. Methods: We compared the adaptive immune response of thrice-vaccinated individuals following Omicron breakthrough infection with those of unvaccinated Omicron-infected and thrice-vaccinated uninfected individuals. Plasma antibodies against Omicron were assessed by normal and competitive versions of ELISA and plaque reduction neutralization assay. Omicron-spike specific memory B and T cells were assessed by flow cytometry. Results: Our data demonstrate higher plasma neutralization potency in vaccinated individuals with Omicron breakthrough compared to the control groups (p<0.001). The levels of Omicron-spike-specific memory B and T cells were comparable between the groups. Importantly, the proportion of antibodies binding mutated regions of the Omicron spike protein was lower in the breakthrough infection group compared to the uninfected vaccinated group (p<0.0001) and equal compared to the vaccinated uninfected group. The same was also true for the proportions of spike-specific IgG+ B cells (p<0.001) and Omicron spike-specific CD4 T cells (p<0.01) targeting regions mutated in the Omicron variant. No significant differences were observed for CD8 T cells. Conclusion: Our findings suggest that Omicron breakthrough infection increases the plasma neutralization potency but not Omicron-specific B and T cell levels in previously vaccinated individuals. Both humoral and cellular responses against the Omicron are mostly a recall of preexisting vaccine induced memory rather than de novo response towards the mutated regions of the spike protein. variants alone to maximize the response to circulating strains The figure, table, or graphic for this abstract has been removed..

higher IgG titres to 229E (p=0.01), NL63 (p=0.003), OC43 (p=0.004) and HKU1 (p=0.004) spike proteins compared to N-unreactive samples. Conclusion: Cumulative exposure to seasonal coronaviruses with age in The Gambia likely resulted in a large proportion of adults possessing anti-SARS CoV-2 nucleocapsid IgG antibodies prior to the COVID-19 pandemic. The exact viral source of this cross-reactivity and the functional relevance of binding antibody responses to nucleocapsid protein remain unknown. Ongoing work that will be presented includes reactivity to HCoV nucleocapsid proteins and the degree of antibody-dependent cellular cytotoxicity (ADCC) activity to SARS-CoV 2 nucleocapsid that may be relevant in viral control. Sarbecovirus Ferritin Nanoparticle Vaccines as Protein or mRNA-LNP Elicit Broad Immunogenicity M Gordon Joyce 1 , Sandra V. Mayer 1 , Philip Davidson 2 , Paul Thomas 1 , Daniel C. Douek 3 , Monica Wu 2 , Nicholas Clark 2 , Amita Vaidya 2 , William Warren 2 , Natalie Anosova 2 , Valerie Lecouturier 4 , Sandhya Vasan 1 , Nelson L. Michael 5 , Natalie Collins 6 , for the Sarbecovirus Ferritin Nanoparticle Study Group 1 Henry M. Jackson Foundation, Silver Spring, MD, USA, 2 Sanofi, Waltham, MA, USA, 3 National Institutes of Health, Bethesda, MD, USA, 4 Sanofi, Marcy l’Etoile, France, 5 Center for Infectious Diseases Research, Silver Spring, MD, USA, 6 Emerging Infectious Diseases Branch, Silver Spring, MD, USA Background: The need for SARS-CoV-2 next-generation vaccines is clear. Early in the COVID-19 pandemic, we designed and characterized four categories of engineered ferritin nanoparticle immunogens based on the WA- 1 sequence that recapitulate the structural and antigenic properties of prefusion SARS CoV-2 Spike (S), S1, and RBD. A lead candidate, Spike-Ferritin nanoparticle (SpFN) adjuvanted with a liposomal-saponin adjuvant (ALFQ) was subsequently assessed in a Phase I study in humans showing broad immunogenicity to VoCs. Building on that work, we have developed novel immunogen designs that have increased antigenic diversity and are delivered as mRNA-LNP immunogens. This study aims to understand the breadth of sarbecovirus immune response that can be elicited using either adjuvanted protein or mRNA platforms. Methods: Designs based on Spike and RBD proteins contain antigenic matter from up to four different sarbecovirus strains. To further increase the vaccine immunogen diversity, formulations including two or more of these antigen designs were combined as cocktail or mosaic immunogens to further increase the vaccine immunogen diversity. These immunogens were either produced as proteins in mammalian cells or expressed in vivo as mRNA encapsulated in LNP. Groups of 8-10 naïve male and female C57BL/6 mice were immunized 2-3 times, followed by serum antigen binding and pseudovirus neutralization assessment. Results: Immunogens in both protein-ALFQ or mRNA format elicited broad and robust neutralizing responses. The mRNA formulations containing BQ.1.1 immunogens (either singly or in combinations) elicited potent neutralizing responses against all Omicron virus strains assessed. Vaccine candidates combining antigens from three sarbecovirus strains elicited high ID 50 GMT titers against all sarbecovirus strains tested, including heterologous pseudoviruses not included in the vaccine. Of further note, following two immunizations, ID 50 GMT titers of 19,200 and 1,400 against heterologous Omicron BA.5 and XBB.1.5 respectively were observed in mice immunized with this trivalent combination. Conclusion: The ferritin platform either as a protein or mRNA format provides a potent platform for pan- sarbecovirus vaccine development. Funding statement: This work was funded by the Walter Reed Army Research Institute, the Henry Jackson Foundation, Sanofi, and the National Institute of Health. Disclosure: PD, MW, NC, AV, WW, NA, VL are Sanofi employees and may hold shares and/or stock options in the company. Immune Responses to an Original/BA 4-5 Bivalent Booster of SARS-CoV 2 mRNA Vaccine in PWH on ART Matteo Augello 1 , Valeria Bono 1 , Roberta Rovito 1 , Alessandro Tavelli 2 , Camilla Tincati 1 , Alessandra Vergori 3 , Anna Maria Azzini 4 , Elda Righi 4 , Andrea Antinori 3 , Evelina Tacconelli 4 , Antonella D'Arminio Monforte 2 , Giulia Marchetti 1 , for the VaxICONA-ORCHESTRA Study Group 1 University of Milan, Milan, Italy, 2 Icona Foundation, Milan, Italy, 3 Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, 4 University of Verona, Verona, Italy Background: In the current Omicron era of COVID-19 pandemic, boosters with variant-adapted mRNA vaccines are recommended for fragile populations to provide broad protection against newly emergent SARS- CoV-2 variants. While previous studies showed enhanced neutralization against Omicron sub-lineages after a bivalent booster, data on T-cell immunity are limited, especially in PWH. We assessed humoral and T-cell responses to an original/BA.4-5 booster in this population.

387

Poster Abstracts

389

388

92

CROI 2024