Immune correlates of protection following Rift Valley fever virus vaccination

Abstract

Rift Valley fever virus (RVFV) is a hemorrhagic fever virus with the potential for significant economic and public health impact. Vaccination with an attenuated strain, DelNSsRVFV, provides protection from an otherwise lethal RVFV challenge, but mechanistic determinants of protection are undefined. In this study, a murine model was used to assess the contributions of humoral and cellular immunity to DelNSsRVFV-mediated protection. Vaccinated mice depleted of T cells were protected against subsequent challenge, and passive transfer of immune serum from vaccinated animals to naïve animals was also protective, demonstrating that T cells were dispensable in the presence of humoral immunity and that humoral immunity alone was sufficient. Animals depleted of B cells and then vaccinated were protected against challenge. Total splenocytes, but not T cells alone, B cells alone, or B + T cells harvested from vaccinated animals and then transferred to naïve animals were sufficient to confer protection, suggesting that multiple cellular interactions were required for effective cellular immunity. Together, these data indicate that humoral immunity is sufficient to confer vaccine-mediated protection and suggests that cellular immunity plays a role in protection that requires the interaction of various cellular components.

Use of Hu-PBL Mice to Study Pathogenesis of Human-Restricted Viruses

“…Hu-PBL models have the advantage of faithfully mimicking the so-called patient memory immune response in the mouse. In particular, it was demonstrated that the hu-PBL/DC model enables the investigation of correlates of immunity in EVD survivors [ 43 ], which might be expanded to the investigation of other viral infections, such as infection with Rift Valley fever virus (RVFV) [ 116 ], SARS-CoV-2 infection and reinfection [ 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ], or yellow fever virus (YFV) infection [ 127 ]. In this way, it is also possible to analyze the interactions that take place between the immune cells throughout the development of a specific disease given that they have been demonstrated to enable the sequential engraftment of distinct cell types [ 39 ].…”

Perspectives of Next-Generation Live-Attenuated Rift Valley Fever Vaccines for Animal and Human Use

“…For RVFV, the virus neutralization test based on a virulent virus is considered a gold standard for the detection of neutralizing antibodies; however, progress is being made with neutralization tests using attenuated strains, virus-like particles or pseudotyped virus particles that can be performed under BSL-2 conditions [ 77 ]. In humans, clear T-cell-based correlates of protection have yet to be described, though a recent study indicated a clear role for cellular immunity in protection through the interaction of various cellular components [ 78 ]. The concept for any RVF vaccine to differentiate naturally infected from vaccinated individuals or animals (e.g., DIVA) is a diagnostic challenge that may best be assessed as a part of large-scale clinical trials.…”

Humoral immunity to phlebovirus infection

“…The protective capacity of neutralizing antibodies has been demonstrated through passive transfer of convalescent sera to susceptible animals 1,38 . Furthermore, data from vaccine studies have demonstrated that high serum‐neutralizing titers are sufficient to provide protection in animal challenge models 40 . Study of individuals exposed to RVFV occupationally has shown that naturally acquired immunity can be long‐lived, with neutralizing antibodies being readily detectable despite a lack of additional virus exposures 41–43 .…”

“…Study of individuals exposed to RVFV occupationally has shown that naturally acquired immunity can be long‐lived, with neutralizing antibodies being readily detectable despite a lack of additional virus exposures 41–43 . Immune correlates of protection against RVFV have been studied in mice vaccinated with an RVFV attenuated vaccine (DelNSsRVFV) 40 . Mice were protected from lethal RVFV challenge with or without depletion of CD4 + and/or CD8 + T cells, or B cells prior to RVFV challenge.…”

“…Neutralizing antibodies play an important role in virus clearance upon infection and are able to prevent phlebovirus infection in animal challenge models 1,38,40 . While neutralizing epitopes have been identified on the surface glycoproteins of RVFV, SFTSV, and TOSV, mAbs with cross‐binding or cross‐neutralizing activity against multiple phlebovirus families have not been identified.…”