Viruses | Free Full-Text | Vaccination against Rabbit Hemorrhagic Disease Virus 2 (RHDV2) Using a Baculovirus Recombinant Vaccine Provides Durable Immunity in Rabbits

Rabbit hemorrhagic disease virus 2 has spread to 5 continents and has been confirmed in 29 states within the U.S. in addition to two Canadian territories at the time of this publication [28,29]. The disease is characterized by high mortality (60–90%) in domestic and European rabbits and can infect wild lagomorph species with variable results. The economic impact on the rabbit meat industry is significant, not to mention the impact on pet trade and wildlife species of conservation concern. Rabbits are the 3rd most common companion mammal behind dogs and cats in the U.S., and as of 2017, account for roughly half a million food animals on more than 4000 farms [30]. Rabbits are also raised for show exhibition, manure production, fur/pelts, and as an alternative meat for pet food. Other countries consider rabbit meat a mainstay as a food source, including China, Korea, and much of Europe. In addition to pets and farm animals, rabbit hunting is a common practice worldwide, and in the U.S., approximately 1.3 million people hunt rabbits each year, contributing to the roughly $1.6 billion revenue generated by small game hunters [31]. Therefore, the need to manage and minimize the impact of RHDV2 cannot be overstated.

Vaccines against RHDV2 have been in existence since 2016 and have been highly efficacious in preventing disease for vaccinated animals [15]. In places where RHDV and RHDV2 cocirculate, inactivated multivalent vaccines like Filavac are deployed [15]. However, in the U.S., only RHDV2 is endemic and as such, vaccines can target this genotype specifically. The baculovirus-vectored recombinant vaccine produced by Medgene has been shown to be highly efficacious in preventing disease, and the current study not only confirms this efficacy, but also demonstrates lasting immunity over 6 months post-vaccination. Indeed, other baculovirus-vectored RHDV2 vaccines have shown similar results, with immunity lasting up to 14 months in most individuals [21], suggesting that this vaccine platform elicits strong humoral and cell-mediated immunity. In this study, antibody titers coupled with a strong protective response against infection suggest that humoral immunity is highly indicative of a protective response. Furthermore, antibody titers remained at the level of protection for a full 12 months, with a dramatic increase in titers following a booster, suggesting that annual boosters would provide a robust increase in immune response and are highly likely to confer lasting immunity. Interestingly, one rabbit (#677) that received only a single dose of the vaccine failed to seroconvert, while all rabbits receiving a prime-boost series developed a strong antibody response, thereby indicating that a two-dose series is ideal for optimum response. In the prior study {26}, vaccination prevented disease but did not prevent infection, as was confirmed by the presence of RHDV2 RNA in the livers of vaccinated and infected animals 10 days post-infection; but in the current study, all but one vaccinated rabbit was able to completely clear viral RNA from the liver by 10 days post-infection. The major difference between these two studies, in addition to time between vaccination and challenge, is that the first study utilized group housing of vaccinates and controls, so it is possible that vaccinated animals were continually exposed to infectious virus material shed by control animals into the environment and therefore received multiple “inoculations” during the course of the study. RHDV can persist in the environment and maintain infectivity for at least 91 days, and viral RNA can also persist in animals that survive infection for 3 months, so it is unsurprising to find evidence of infection in these vaccinated animals [32,33]. Importantly, in the current study, none of the vaccinates displayed any signs of clinical disease, while 95% (18/19) of the placebo-vaccinated controls died or were euthanized due to severe clinical disease during this same time frame. These results clearly demonstrate that vaccination is highly effective in preventing disease and disease-associated mortality.

Because RHDV2 can persist in the environment, and because vaccination does not necessarily prevent infection and subsequent shedding of infectious virus, the only way to prevent the spread of this virus within a rabbit facility is to ensure that all rabbits are vaccinated. Based on the PCR results from the livers of vaccinated-infected animals, it is likely that vaccinated animals shed less virus and for a shorter period of time than animals that are infected and recover, but since we did not specifically test rabbit feces or other bodily fluids for presence of infectious virus, we cannot confirm that vaccinates are not shedding. Previous studies show that inoculating rabbits with fecal material from RHDV2-infected rabbits can result in disease, so it is likely that rabbits can acquire infection from coming into contact with feces or other material from infected rabbits [32]. Furthermore, lagoviruses are extremely hardy and can persist in the environment on feces and in infected tissue for months [34,35], so current biosecurity measures need to consider that bedding and cages are infectious unless decontaminated using bleach or other proven methods of inactivation. This is particularly important for rabbits who attend shows or fairs and are housed in contact with other rabbits or their bedding. However, all rabbits that are housed outdoors or in any facility where they may encounter wild rabbits would benefit from vaccination. It is unlikely that RHDV2 is eradicable from the U.S. or any country where wild rabbits have been infected, and vaccination of wild rabbits is not a feasible option for controlling the spread of the virus, so ultimately the burden rests on rabbit owners to mitigate this risk. Future studies should focus on whether or not vaccinated animals are capable of shedding infectious virus following exposure to RHDV2 and should characterize the duration of shedding of infectious material. At present, the most viable option for preventing disease is to vaccinate all individuals at risk of exposure.