Protection Against CNS-Targeted Rabies Virus Infection is Dependent upon Type-1 Immune Mechanisms Induced by Live-Attenuated Rabies Vaccines

Abstract

Rabies remains a major public health issue worldwide, especially in developing countries where access to medical care can represent a real challenge. While there is still no cure for rabies, it is a vaccine-preventable disease with pre- and post-exposure prophylaxis regimens approved by the World Health Organization (WHO). However, many rabies-exposed individuals have limited access to vaccines and virus-neutralizing antibodies approved for post-exposure prophylaxis. Unfortunately, any delay in the administration of these reagents can have lethal consequences. This highlights the need to develop cost-effective immunological reagents with a greater window of efficacy. Live-attenuated vaccine strains of rabies virus presents a potential treatment in filling this gap. We show here that immunization with live-attenuated vaccines provide long-lasting rabies immunity, superior to the protection induced by inactivated vaccines. In the absence of an immunostimulatory adjuvant, vaccination with multiple doses of inactivated rabies virus induces a type-2 immune response. This type of immunity is highly effective at inducing neutralizing antibody but has limited efficacy in clearing the virus from central nervous system (CNS) tissues. In contrast, a single infection with live-attenuated rabies vaccine safely drives a type-1 immune response, associated with both the production of a neutralizing antibody and the clearance of wild-type rabies virus from CNS tissues. These results indicate that live-attenuated rabies strains have the potential to be more effective in post-exposure prophylaxis than conventional inactivated vaccines.

Comparable Long-Term Rabies Immunity in Foxes after IntraMuscular and Oral Application Using a Third-Generation Oral Rabies Virus Vaccine

“…It is generally assumed that immunization with inactivated RABVs elicits a species independent type-2 response with high levels of type-2-associated IgG1 RABV-specific antibodies [ 28 , 29 ], while live attenuated RABV vaccines induce type-1 responses [ 36 , 62 ]. The results presented here as well as in previous studies support the predominance of type-1 immunity protection of live-attenuated RABVs and modified live vectored RABV vaccines in vaccinated mice [ 63 ] and carnivores, including foxes [ 36 , 37 , 48 ], since independent of the route of administration the immune response to SPBN GASGAS was mainly IgG2 driven ( Figure 3 ). This was also reflected by the significant correlation between total IgG and IgG2 levels, which are critical for protection against lethal rabies infection [ 64 , 65 ] with VNA and binding antibodies ( Figure 4 ).…”

“…Considering that wild-type RABV is efficiently protected from clearance by an almost exclusive intraneuronal spread, the capacity to stimulate RABV-specific type-1 immunity mediating antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) is an essential basis for an effective rabies vaccine [ 33 ]. Therefore, single immunization with live-attenuated vaccine confers superior, long-lasting protection against wild-type virus challenge compared to inactivated vaccines [ 36 ]. It seems that the anti-dog-IgG2 used in our study recognizes an IgG subclass that is thought to induce strong ADCC activity, whereas dog IgG1 does apparently not [ 63 ].…”

“…Initiation of CD4+ and CD8+ T cell responses after RABV infection independent of the virus used has been described [ 34 ], with live RABV vector vaccines able to elicit both a type 1 and 2 immune response [ 35 ]. Hence, immunization with live-attenuated vaccines is supposed to provide long-lasting rabies immunity, superior to the protection induced by inactivated vaccines [ 36 ]. Most of the studies to evaluate the innate host immune responses to live-attenuated RABVs, including oral rabies vaccines, were carried out in small laboratory animals, not the natural hosts for the rabies virus.…”

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

“…Previous studies reported that MPLA could induce a strong Th1 response, which was associated with the induction of IgG2a and IgG2b antibodies in mice [20,21]. The Th1 response was associated with both the production of VNA and the clearance of wild type RABV from the central nervous system (CNS) [51]. The RABV-specific IgG isotyping test revealed that MPLA-supplemented inactivated rabies vaccines mainly induced Ig class switching to IgG2a and IgG2b, which implied a beneficial effect of adjuvant MPLA on the inactivated rabies vaccine.…”

Special Issue: Rabies Symptoms, Diagnosis, Prophylaxis, and Treatment

“…The blood–brain barrier is a formidable concern when trying to deliver certain biologics to the CNS, especially in the treatment of encephalitis. To this end, data on further technological improvement for the use of a highly attenuated rabies virus recombinant vaccine in disease prevention and potential treatment is offered by Lebrun et al [ 23 ]. Needs for improved passive immunity via alternative methods to polyclonal immune globulins, such as monoclonal antibodies (MAb), were first described at the end of the 1970s.…”