Fragment crystallizable receptor-effector functions as a key correlate for pan-sarbecovirus vaccine development

In a recent study posted to the bioRxiv* preprint server, researchers elucidated pan-sarbecovirus immune protection mechanisms by utilizing a Venezuelan equine encephalitis virus-vectored vaccine panel that covered bat strains to human strains.

Study: Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination. Image Credit: Andrii Yarovsky/Shutterstock
Study: Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination. Image Credit: Andrii Yarovsky/Shutterstock

Studies have reported on global and regional epidemics caused by sarbecoviruses; however, the cross-protection mechanisms driven by sarbecoviruses’ spike (S) proteins are not well-characterized, albeit critical in order to develop pan-sarbecovirus vaccines.  It has been reported that antibody fragment crystallizable receptor (FcR) facilitated effector-type events are essential to generate protective immunity. FcRs have high affinities for immunoglobulin G (IgG) antibody subtypes.

About the study

In the present study, researchers used the virus replicon particle 3526 (VRP3526) of the Venezuelan equine encephalitis virus as an investigational platform for determining cross-immune protection mechanisms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) CoV S and pre-emergent CoV S vaccinations in murine models, with subsequent high-dose SARS-CoV-2 challenge.

VRPs were generated expressing S proteins of multiple alpha-CoVs and beta-CoVs, including common cold-causing CoVs, NL63, HKU1, and OC43, pre-emergent (HKU3, RaTG13, SHCO14, and WIV1), and pandemic sarbecoviruses (SARS-CoV-1, 2). The sarbecovirus S proteins were grouped depending on the similarity of amino acids, which were: clade 1a group (WIV1, SHC014, SARS-CoV), clade 2 group (HKU3), and clade 1b group (SARS-CoV-2 and RaTG13 viruses). Immunofluorescent analysis verified S protein expression among VRP-infected cells. A lethal murine model was used for testing the platform and evaluating the S-elicited cross-protection against coronavirus disease 2019 (COVID-19).

The team immunized BALB/c-type mice with VRP coding different S vaccines and subsequently boosted them with homologous S VRP three weeks post-immunization. After three weeks of boosting, the animals were intranasally challenged with the SARS-CoV-2 MA10 strain. Mice’s body weight was monitored, and their pulmonary tissues were examined for diffuse alveolar damage (DAD), acute lung injury (ALI), and gross discoloration (GLD). The team investigated whether immunization with VRP-expressing common cold human β-CoV S would protect against COVID-19. Cytokine immunoassays were performed to evaluate cytokine responses on the second and fifth days post-challenge.

Aged mice vaccinated with prime and booster VRP doses 3.0 weeks apart were intranasally challenged with [1.0 median lethal dose (LD50)] SARS-CoV-2 MA10 21 days post-booster vaccination. Further, live virus assays were performed to evaluate the titers of neutralizing antibodies. Cross-correlative analysis was performed to delineate immune protective signatures generated by VRP S vaccinations. Further, the capacity of VRP S sera to induce ADCP (antibody-dependent cellular phagocytosis) and ADNP (antibody-dependent neutrophil phagocytosis) against the S protein of SARS-CoV-2 was evaluated. Passive transfer experiments were conducted to evaluate FcR effector function in VRP S cross-protection in vivo, using FcR-deficient BALB/c mice challenged with lethal MA10 doses.

Results

Venezuelan equine encephalitis VRP assembly generated elevated titer vaccines for potent in vivo CoV S protein expression. VRP-vectored sarbecoviruses’ S proteins protected against COVID-19 SEVERITY in young and aged mice, and VRP SARS-CoV-2 S protected against heterologous sarbecovirus infection. VRP S vaccinations induced non-neutralizing, cross-reactive antibodies and antibody-mediated protection via the Fc effector mechanisms. Vaccination did not prevent viral replication but protected against severe outcomes among HKU3- and SARS-CoV-2-challenged mice.

S protein vaccines primarily induced highly S1-targeted homologous neutralizing antibodies without significant cross-neutralization. Further, non-neutralizing antibody functions mediating cross-virus protection were found to be mechanistically associated with S2- and FcgR4-binding Ig2a antibodies despite a robust homologous protection profile. VRP-comprising homologous SARS-CoV-2 S vaccines protected against loss of weight, severe infection, and virus replication post-homologous challenge. The analysis findings indicated FcR-driven S2-targeting cross-protective mechanisms, including ADCP.

VRP SARS-CoV-2 S vaccine was the only vaccine to almost fully protect against homologous replication of the virus. VRP RaTG13 S vaccinations reduced viral titers by 10.0-fold and 1000-fold on the second and fifth days post-infection, respectively, compared to controls. In VRP HKU3 S-vaccinated animals, MA10 strain titer and clade 1a virus titer values were lowered significantly post-infection. Clade 1b and clade 2 vaccines protected against lung damage and COVID-19 severity. Sarbecovirus S proteins vaccines induced type 1 helper T (Th1) responses with marked vaccine-antigen-targeted grouping in IgG2a to IgG1 ratios.  Fc-mediated, non-neutralizing functions such as ADCP and antibody-dependent complement deposition (ADCD) ranked the highest.

S2 detection by VRP S sera was linked to Fc-effector-mediated functions, whereas S1 correlated robustly with FcgR4. Heptad repeat region 2 (HR2), fusion peptides (FP), and the stalk subareas majorly drove IgG2a recognition. Within S2, HR2 was fully conserved between the sarbecovirus S proteins, whereas HR1 varied. Passive antibody transfer mitigated severe COVID-19. VRP HKU3 S IgG2a binding to HR1 and RaTG13 sera binding to S2 significantly correlated with protection from infection. The in vivo protection by VRP S vaccines was S2-linked.

Overall, the study findings highlighted the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs and showed that the non-neutralizing-type Fc function primarily drove VRP S antibody-regulated cross-sarbecovirus protection.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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