Transmissible and Transferable Vaccines
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A new animal vaccination strategy has been proposed to address the epidemiology problem of zoonotic spillover. Pathobiological scientists are exploring the possibility of transmissible vaccines that spread through populations much like their target pathogens.
Zoonotic pathogens are diseases that originate in animals. Many of these diseases have the potential to spread to humans, or have already done so. SARS-CoV-2, the virus that causes COVID-19, is only one of the recent diseases caused by zoonotic spillover. Infectious disease experts are aware of many animal populations – such as bats – that can act as reservoirs for zoonotic viruses. Vaccination of individual animals is only one of the many strategies employed to slow the spread of these pathogens.
Vaccinate animals to prevent disease spread
“SARS, MERS, Ebola, Nipah and an array of arenavirus infections sporadically spillover into human populations and are often contained only as a result of their poor transmission in human hosts, coupled with intense public health control efforts in the early stages of an emerging epidemic,” say Scott Nuismer and James Bull, computational biology professors at the University of Idaho. Nuismer, Bull and their research groups have performed extensive modeling of viral and vaccine transmission.
Stopping these diseases before they can spread to humans would result in significant decreases in loss of life and in the economic costs of epidemics. There are currently two main ways to control zoonotic pathogens before they can spread disease to humans: culling diseased animal populations, and vaccinating vulnerable animal populations through catch and release programs or through distributing vaccine-laced baits. Both methods have their drawbacks, especially when the animal populations in question have rapid turnover or are in hard-to-reach locations. Transmissible vaccines would significantly decrease the amount of effort needed to vaccinate animals.
There are two methods to spread vaccines from one animal to others:
Are developed from live viruses, injected into the animal, and can be passed to indefinite numbers of other animals.
Are applied to the animal as an edible paste, and spread to other members of the population through activities such as social grooming. Transferable vaccines, like vaccine-laced baits, are not contagious and will not spread as much as strongly transmissible vaccines.
Attenuated or recombinant vaccines
Virologists are looking at two types of vaccines as potential candidates for transmissible vaccine programs: attenuated and recombinant vector vaccines.2
Live attenuated vaccines are made from a weakened version of the pathogenic virus, which can replicate without causing disease. Viral growth rate is reduced through genetic manipulation. However, as Nuismer and Bull point out, virulence and transmissibility are generally linked. This means that attenuated vaccines that are too weak to cause disease may also be unable to transmit to other hosts.
Recombinant vector vaccines use a benign virus, into which pieces of the pathogen’s genome have been inserted. The choice of the benign vector depends on many factors, including its own transmission rate and whether it is already present in the target species. Immunity to either the vector or the pathogen will slow the spread of the vaccine. The transgenic inserts must have immunogenic properties, but must also be stable enough to survive through self-replication.
An emerging technology
Transferable vaccines have risks that are similar to current campaigns with vaccine-laced baits and are therefore well understood.
Transmissible vaccines, on the other hand, are an emerging technology that needs further risk evaluation. One such risk is that increased replication allows more opportunities for evolution of attenuated vaccines back to virulence. Evolutionary change during transmission is inevitable, because the vaccine has to self-replicate to spread. Attenuated viruses are weakened due to a few nucleotide substitutions in their genetic code. These viruses may revert back to wild-type virulence after replication mutations undo these genetic changes. This has been reported with the oral polio vaccine in populations with low poliovirus immunity, leading to outbreaks.3 Due to the risk of reverting back to wild-type pathogen, Nuismer and Bull suggest that attenuated vaccines may be best used for combating pathogens that do not infect humans: “Developing safe but highly transmissible attenuated vaccines may be challenging.”
A recombinant vaccine can mitigate this virulence risk, because evolutionary mutations are likely to cause the vaccine to revert back to the original benign virus. However, this means they are also likely to lose the ability to function as a vaccine. Increasing the number of pathogen antigens inserted into the vector’s genome may help to increase the lifetime of the vaccine.
“Recombinant vaccines are a priori the most promising approach for a transmissible vaccine,” say Nuismer and Bull. However, they point out that, if a recombinant vaccine uses a novel vector to avoid immunity already present in a population, there is still a risk of evolution into a pathogen.
Professor Jorge Osorio agrees that, in general, recombinant vaccines are safer than attenuated vaccines. Osorio is a University of Wisconsin professor in the department of pathobiological sciences in the School of Veterinary Medicine, with experience in vaccine development for many different emerging infectious diseases. He prefers to work with transferable vaccines because of the risks inherent in transmissible vaccines. “One of the [most] important aspects of vaccines is to retain safety,” he says. There’s a chance that the viruses used to create these vaccines could spread to populations or species outside the target population, including to humans.
Nuismer and Bull describe potential ways to mitigate these risks, in addition to using recombinant vector vaccines. The use of species-specific vectors could minimize the chance that these viruses could spread outside the target population. Vaccine design could include self-regulatory mechanisms that keep transmission low enough that the virus would eventually self-extinguish. Tests of species-specific vaccines would be performed in related reservoir species, to determine the likelihood of cross-species spillover and effectiveness.
Promising computational models
In 2001, a successful trial of a recombinant vaccine for rabbit hemorrhagic disease in an isolated population of wild rabbits was reported in the journal Vaccine.4 Half of the rabbit population was injected with the vaccine before release. One month later, half of the uninoculated population was found to be vaccinated through transmission of the vaccine. In 1994, similar methods were suggested to sterilize feral mammal populations in Australia.5
Despite these early tests, effective transmissible vaccines are still largely theoretical. Most papers published on this topic are computational, describing promising mathematical models that suggest transmissible vaccines can be used successfully for zoonotic disease control. Mathematical models have limitations that will need to be examined in laboratory and field tests, the papers explain. These models make several assumptions about vector transmissibility and vaccine infection that can only be tested in vivo. Ideal vaccine vectors will need to infect hosts despite the potential presence of an existing infection or immunity.
Initial development of transmissible vaccines would be most effective when targeting well-known zoonotic pathogens, such as rabies. As Nuismer and Bull point out, rabies is a good target to start with because it already has a wildlife vaccine that just needs to be made self-disseminating. However, to effectively eliminate rabies through this method would require a different vaccine to target each reservoir species.
Osorio’s group is currently working on the development of a transferable rabies vaccine, which would be applied to bats in a jelly-like substance. The group suggested this method on white-nose syndrome and tested the theory using fluorescent biomarkers that same year.6,7 The methods and results of the rabies vaccine test will be described in an upcoming paper, Osorio says.
Human application is unlikely
Some live human vaccines already have some transmissibility, says Osorio. This can happen with inoculations that result in attenuated viruses being present in mucosal membranes, such as a nasal spray flu vaccine. However, he warns that there are still too many risks involved in transmissibility for it to be a desirable quality in a wildlife vaccine. Incidents such as the polio vaccine reverting to wild-type virulence inspire careful risk assessment.
Vaccine researchers appear to agree that transmissible vaccines, at least in initial applications, should be targeted toward animal populations. Identifying high-risk pathogens before they emerge would be ideal, but this is hard to do reliably, even with wildlife surveillance and virus characterization. Therefore, transmissible vaccines will be most effective when building on the previous research on well-known zoonotic viruses.
Biological information about the reservoir species will help scientists to choose the ideal timing for vaccination and which individual animals are likely to spread the vaccine the farthest. Vaccine developers will also need to decide between transmissible and transferable vaccines, and design their vector for minimum risk and maximum effectiveness. “Our results suggest that the durability of weakly transmissible vaccines tends to be limited by competition with the pathogen while that of strongly transmissible vaccines is limited by evolutionary stability,” say Layman, Tuschhoff and Nuismer.
Nuismer and Bull add that vector choice is critical. “Ideal vectors will have large, insert tolerant genomes, possess low mutation rates, and will not be unduly limited by trade-offs between important epidemiological and evolutionary parameters.” A recent paper by Nuismer’s group evaluates the potential to use betaherpesviruses as vectors for recombinant vaccines.8 These viruses are good candidates for vaccine vectors “due to their broad taxonomic distribution across important groups of reservoir species, high species specificity, and mild or undetectable virulence in most natural reservoirs”.
Extensive research will be required to achieve successful transmissible vaccines. “The successful application of recombinant transmissible vaccines will likely require – at a minimum – the consideration of efficacy, transmission rates, antigenic redundancy, and mutation rates,” say Nuismer and Bull.
1. Nuismer SL, Bull JJ. Self-disseminating vaccines to suppress zoonoses. Nat Ecol Evol. 2020;4(9):1168-1173. doi: 10.1038/s41559-020-1254-y.
2. Layman NC, Tuschhoff BM, Nuismer SL. Designing transmissible viral vaccines for evolutionary robustness and maximum efficiency. Virus Evolution. 2021;7(1). doi: 10.1093/ve/veab002.
3. Famulare M, Chang S, Iber J, et al. Sabin vaccine reversion in the field: a comprehensive analysis of sabin-Like poliovirus Isolates in Nigeria. Sandri-Goldin RM, ed. Journal of Virology. 2016;90(1):317-331. doi: 10.1128/jvi.01532-15.
4. Torres JM, Sánchez C, Ramı́rez MA, et al. First field trial of a transmissible recombinant vaccine against myxomatosis and rabbit hemorrhagic disease. Vaccine. 2001;19(31):4536-4543. doi: 10.1016/s0264-410x(01)00184-0.
5. Tyndale-Biscoe C. Virus-vectored immunocontraception of feral mammals. Reprod Fertil Dev. 1994;6(3):281. doi: 10.1071/rd9940281.
6. Rocke TE, Kingstad-Bakke B, Wüthrich M, et al. Virally-vectored vaccine candidates against white-nose syndrome induce anti-fungal immune response in little brown bats (Myotis lucifugus). Sci Rep. 2019;9(1). doi: 10.1038/s41598-019-43210-w.
7. Bakker KM, Rocke TE, Osorio JE, et al. Fluorescent biomarkers demonstrate prospects for spreadable vaccines to control disease transmission in wild bats. Nat Ecol Evol. 2019;3(12):1697-1704. doi: 10.1038/s41559-019-1032-x.
8. Varrelman TJ, Remien CH, Basinski AJ, Gorman S, Redwood A, Nuismer SL. Quantifying the effectiveness of betaherpesvirus-vectored transmissible vaccines. PNAS. 2022;119(4):e2108610119. doi: 10.1073/pnas.2108610119.