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人畜共患溢出。传染病专家知道许多动物种群 - 例如bats- 可以充当人畜共患病毒的储层。单个动物的疫苗接种只是减缓这些病原体传播的众多策略之一。

疫苗接种动物以防止疾病传播

“ SARS，MERS，EBOLA，NIPAH和一系列体育症病毒感染偶然地溢出到人类人群中，通常仅由于其在人类宿主中的不良传播而导致的，再加上新兴流行病的早期阶段的强烈公共卫生控制工作，”说Scott NuismerandJames 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.

减毒或重组疫苗

病毒学家正在看两种类型的疫苗作为潜在候选者for transmissible vaccine programs: attenuated and recombinant vector vaccines.²

活疫苗的活疫苗由病原病毒的弱版制成，可以复制而不会引起疾病。通过基因操纵，病毒生长率降低。但是，正如Nuismer和Bull指出的那样，毒力和透气性通常是联系的。这意味着减弱过于弱而无法引起疾病的疫苗也可能无法传播给其他宿主。

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.

一种新兴技术

可转移的疫苗的风险类似于当前带有疫苗诱饵的活动，因此被充分理解。

可传播的疫苗, 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 beenreported脊髓灰质炎病毒免疫力低的群体中，口服脊髓灰质炎疫苗，导致暴发。³Due to the risk of reverting back to wild-type pathogen, Nuismer and Bull建议这种减毒的疫苗可能最能用于打击不感染人类的​​病原体：“开发安全但高度可传播的衰减疫苗可能具有挑战性。”

重组疫苗可以减轻这种毒力风险，因为进化突变可能导致疫苗恢复回原始的良性病毒。但是，这意味着他们也可能失去充当疫苗的能力。增加插入载体基因组中的病原体抗原数量可能有助于增加疫苗的寿命。

Nuismer和Bull说：“重组疫苗是传播疫苗的先验方法。”但是，他们指出，如果重组疫苗使用新型媒介来避免人群中已经存在免疫力，则仍然存在进化为病原体的风险。

豪尔赫·奥索里奥教授同意，通常，重组疫苗比减毒疫苗更安全。奥索里奥（Osorio）是威斯康星大学兽医学院病理生物学科学系教授，在许多不同的新兴传染病方面具有疫苗开发方面的经验。由于可传染性疫苗固有的风险，他更喜欢使用可转移的疫苗。他说：“疫苗的最重要方面之一是保留安全。”这些病毒用来创建这些疫苗的可能性可能会传播到目标人群以外的种群或物种，包括人类。

Nuismer和Bulldescribepotential 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.

有希望的计算模型

2001年，在孤立的野兔种群中，重组疫苗针对兔出血性疾病的成功试验是reportedin the journal疫苗。⁴释放前将一半的兔子种群注入疫苗。一个月后，发现一半的无接种人群通过疫苗传播接种疫苗。在1994年，类似方法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 testedin vivo。Ideal vaccine vectors will need to infect hosts despite the potential presence of an existing infection or immunity.

在靶向众所周知的人畜共患病原体（例如狂犬病）时，可传染性疫苗的初步发育将是最有效的。正如Nuismer和Bull所指出的那样，狂犬病是一个很好的目标，因为它已经有了一种野生动植物疫苗，只需要使自我播种。但是，通过这种方法有效消除狂犬病将需要不同的疫苗才能靶向每个储层物种。

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方法on white-nose syndrome and tested the theory using fluorescent biomarkersthat same year。^6,7Osorio说，狂犬病疫苗测试的方法和结果将在即将到来的论文中描述。

人类应用不太可能

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.

疫苗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,”说Layman，Tuschhoff和Nuismer。

Nuismer和Bulladd 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.” Arecent纸by Nuismer’s group evaluates the potential to use betaherpesviruses as vectors for recombinant vaccines.⁸这些病毒是疫苗向量的良好候选者，“由于它们在重要的水库物种，高物种特异性以及大多数天然储层中的轻度或不可检测的毒力中，它们的分类分布广泛”。

需要进行广泛的研究以实现成功的传播疫苗。Nuismer和Bull说：“重组可传播疫苗的成功应用可能至少需要考虑功效，传输速率，抗原冗余性和突变率。”

References:

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.病毒进化。2021;7(1). doi:10.1093/ve/veab002。

3.Famulare M，Chang S，Iber J等。现场萨宾疫苗的恢复：尼日利亚的萨宾风病毒分离株的综合分析。Sandri-Goldin RM编辑。病毒学杂志。2016;90(1):317-331. doi:10.1128/jvi.01532-15。

4.Torres JM，SánchezC，Ramı́rez MA等。可传播的重组疫苗针对粘膜瘤病和兔出血性疾病的首次野外试验。疫苗。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等。荧光生物标志物证明了可扩展的疫苗控制野生蝙蝠传播的前景。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。量化贝代瑟病毒载体的透射疫苗的有效性。PNAS。2022; 119（4）：E2108610119。doi：10.1073/pnas.2108610119。