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，”sayScott Nuismerand詹姆斯·布尔，爱达荷大学的计算生物学教授。Nuismer，Bull及其研究小组对病毒和疫苗传播进行了广泛的建模。

在这些疾病传播之前停止这些疾病将导致生命损失和流行的经济成本大幅下降。当前有两种主要方法可以控制人畜共患病原体，然后才能将疾病传播给人类：挑剔患病的动物种群，并通过捕获和释放程序或通过分发疫苗系列的诱饵来接种脆弱的动物种群。两种方法都有缺点，尤其是当有关动物种群的流动迅速或处于难以到达的位置时。可传播的疫苗将显着减少接种动物所需的努力量。

Attenuated or recombinant vaccines

Virologists are looking attwo types of vaccines as potential candidates用于传播疫苗计划：减弱和重组载体疫苗。²

Live attenuated vaccinesare 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.

重组载体疫苗使用良性病毒，将病原体基因组的部分插入其中。良性矢量的选择取决于许多因素，包括其自身的传输速率以及目标物种是否已经存在。对载体或病原体的免疫力将减慢疫苗的扩散。转基因插入物必须具有免疫原性，但也必须足够稳定才能通过自我复制生存。

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。

另一方面，可传播的疫苗是一项需要进一步风险评估的新兴技术。一种这种风险是，增加复制允许更多的机会将衰减的疫苗进化回毒力。在传播过程中的进化变化是不可避免的，因为疫苗必须自我复制才能扩散。由于其遗传密码中的一些核苷酸取代，减弱的病毒被削弱。这些病毒在复制突变后可能会恢复为野生型毒力，这些遗传变化消失了。这是reportedwith the oral polio vaccine in populations with low poliovirus immunity, leading to outbreaks.³Due to the risk of reverting back to wild-type pathogen, Nuismer and Bullsuggestthat 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.

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。

Professor Jorge Osorio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 and Bulldescribe除了使用重组载体疫苗外，还可以减轻这些风险的潜在方法。使用特异性载体可以最大程度地减少这些病毒在目标群体之外传播的机会。疫苗的设计可能包括自我调节机制，以使传播足够低，以至于病毒最终会自我脱离。物种特异性疫苗的测试将在相关的储层物种中进行，以确定跨物种溢出和有效性的可能性。

有希望的计算模型

In 2001, a successful trial of a recombinant vaccine for rabbit hemorrhagic disease in an isolated population of wild rabbits wasreportedin the journalVaccine。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methodswere suggested to sterilize feral mammal populations in Australia.⁵

尽管进行了这些早期测试，但有效的可传染性疫苗仍主要是理论上的。关于该主题的大多数论文都是计算，描述了有希望的数学模型，这些模型表明可传播疫苗可以成功地用于人畜共患病。论文解释说，数学模型的局限性将需要在实验室和现场测试中进行检查。这些模型对矢量传播性和疫苗感染做出了几个假设，只能进行测试in 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 thismethodon white-nose syndrome and tested the theory using fluorescent biomarkers同年。^{6，，，，7}The methods and results of the rabies vaccine test will be described in an upcoming paper, Osorio says.

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.

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,”sayLayman, 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.” ArecentpaperNuismer的小组评估了使用β-病毒作为重组疫苗的向量的潜力。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”。

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.

参考：

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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。

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6。Rocke TE，Kingstad-Bakke B，WüthrichM等。针对白鼻综合征的病毒载体疫苗候选者诱导小棕色蝙蝠诱导抗真菌免疫反应（Myotis lucifugus）。Sci Rep。2019;9(1). doi:10.1038/s41598-019-43210-w。

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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。