Role for mucosal immune responses and cell‐mediated immune functions in protection from airborne challenge with Venezuelan equine encephalitis virus*

Abstract

Venezuelan equine encephalitis virus (VEEV) replicates in lymphoid tissues following peripheral inoculation and a high titre viraemia develops. Encephalitis develops after the virus enters the central nervous system from the blood, with the earliest neuronal involvement being via the olfactory nerve. Following aerosol challenge with virulent VEEV, the virus is thought to replicate in the nasal mucosa and there could be direct entry into the olfactory nerve via infected neuroepithelial cells. Protection from VEEV infection is believed to be primarily mediated by virus specific antibody. The correlation between protection and neutralising serum antibody titres is, however, inconsistent when the virulent virus is administered by the airborne route. This study demonstrates a link between antibody in serum and the nasal mucosa and protection by means of passive immunisation studies. Intra-nasal administration of antibody increased protection against airborne virus in Balb/c mice. Vaccination of mu MT strain mice that do not have functional B cells and cannot produce antibody revealed normal proliferation of spleen cells in vitro and robust cytokine production. Aerosol challenge of mu MT mice demonstrated that complete protection was only achieved when passive immunisation with antibody was supplemented with active immunisation with the TC-83 vaccine strain of the virus. This implies that cell-mediated immune functions are required for protection against airborne challenge with virulent VEEV.

A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates

“…Nevertheless, there have been reports that serum antibodies do not always correlate with protection from an aerosol VEEV challenge. For example, in one passive-transfer study, mucosal antibodies were found to be required for the protection of mice from an aerosol challenge (14). In this study, we did not attempt to measure antibodies present in the nasal or respiratory tract; however, our results clearly indicate that i.m.…”

“…In one study with mice with nonfunctional B cells but normal T-cell activity and cytokine production, complete protection could be achieved only when the passively administered intranasal antibody was accompanied by vaccination with TC-83 (14). The results were interpreted to indicate that the cell-mediated immune responses induced by vaccination with the live-attenuated virus were necessary to achieve protection from aerosol challenges.…”

Treatment of mice with human monoclonal antibody 24h after lethal aerosol challenge with virulent Venezuelan equine encephalitis virus prevents disease but not infection

“…The effective dose of post-exposure F5 nIgG, delivered 24 h PI, was 500 µg for SC VEEV infection or 50 µg for aerosol infection (Table 3). Local production of antibody in the CNS or nasal mucosa may also play a role in protection and continued suppression of viral replication due to persistant viral RNA (Charles et al, 1997; Elvin et al, 2002; Griffin, 2010). Although SINV RNA was detected by RT-PCR for 12 months after infection in mice effectively treated with passive antibody (Levine and Griffin, 1992; Levine et al, 1991), we found no detectable viral RNA 14–28 days PI in brain tissue from mice infected by aerosolized VEEV and treated 24 h PI with 50 µg F5 nIgG.…”

CpG Used as an Adjuvant for an Adenovirus-Based Venezuelan Equine Encephalitis Virus Vaccine Increases the Immune Response to the Vector, But Not to the Transgene Product

“…For example, studies with MT mice point to the importance of cytokine and T-cell activation (16), and ␣␤ TCR-bearing T cells appear to be required for protection (45). However, protection is not achievable in mouse strains unable to generate an antibody response, such as MT-deficient mice (45).…”

“…This replication-defective vector, based on the ad5 serotype, encodes structural proteins of VEEV (E3-E2-6K). When delivered to BALB/c mice by the intranasal route it was capable of inducing mucosal immunity, which is important in protection against airborne VEEV (16), and is able to elicit protective immunity to mice challenged with airborne VEEV (48).…”