To the Editor — Nuismer and Bull1 argue for the development of self-disseminating vaccines for cost-effective immunization of animal reservoirs to prevent zoonotic spillovers. The authors suggest two approaches: ‘transferable’ vaccines, non-contagious vaccines applied to animals and spread through behaviour such as grooming, and ‘transmissible’ vaccines, replication-competent virally vectored vaccines with potential for indefinite transmission across populations.

We agree with Nuismer and Bull that cost-effective vaccination of reservoir populations would be a great asset. Vaccination of animal reservoirs may reduce regular spillover of pathogens such as rabies and Lassa virus, and perhaps in rare cases even zoonotic pathogens with pandemic potential. However, we contend that the substantial safety and security risks around the advancement of transmissible vaccines outweigh potential benefits. While Nuismer and Bull touch on safety concerns around this approach, their brevity is not commensurate to the gravity of the associated safety and biosecurity risks. Instead of transmissible vaccines, we propose that efforts focus on the safer and more predictable transferable vaccine approach to achieve cost-effective vaccination of reservoir populations.

Unpredictability of viral mutations and spread cannot be avoided

Any self-replicating agent released into the wild will be selected for enhanced transmission, underscoring the unpredictable evolutionary risks inherent to the engineering and release of transmissible viruses. Mutations or recombination events with wild viruses may lead to an increase in pathogenicity or host range expansion, including to domesticated animals or humans. To minimize safety risks, Nuismer and Bull propose to develop transmissible vaccines based on recombinant vector viruses specific to the targeted reservoir species and engineering such vectors to feature self-regulatory mechanisms and an R0 below 1. We agree with the authors that properties such as species-specificity and an R0 below 1 would be critical for reducing safety risks. However, conceptually similar safeguards have been tested extensively in laboratory bacteria and viruses, both of which lead to reliable evolutionary escape at relevant population sizes2. Even a virus with low R0 would similarly generate and select for functional mutations if introduced at scale, as demonstrated by genetically divergent vaccine-derived polioviruses arising in areas of low vaccine coverage despite the low R0 of the live poliovirus vaccine3.

The escape rate for transmissible vaccines may be higher than laboratory studies would predict due to the potential for recombination with wild-type viruses. For example, while cytomegalovirus is commonly cited as a very promising vector candidate for transmissible vaccines due to its high species-specificity and its ability for superinfection and reinfection of hosts with pre-existing immunity, herpesviruses are ubiquitous in most species and superinfection favours pervasive recombination of genetic material4.

To ensure that safety risks are minimized during development, the authors propose to evaluate the properties of such vaccines in captured and geographically secluded populations. However, such small-scale testing will by definition lack the numbers required to assess evolutionary stability and species confinement during applications, which will involve circulation in much larger populations. For instance, even if a virus engineered to exhibit an R0 below 1 does not spread at higher rates in small-scale tests, the accumulation of and selection for transmission-enhancing genetic changes over time or in larger populations may enable unwanted spread throughout the target species, including across international boundaries.

Ensuring the safety of larger-scale assessments of the effectiveness, transmission and evolution of such vaccines may not be feasible, as demonstrated by the long history of accidental and deliberate invasion. For example, rabbit haemorrhagic disease virus escaped from a high-security experiment on Wardang Island in 1995, leading to the inadvertent killing of rabbits all over Australia and the subsequent deliberate smuggling of that virus into New Zealand5. Therefore, even carefully designed and tested transmissible vaccines will exhibit unpredictable safety concerns.

Biosecurity risks associated with the development of transmissible vaccines

In addition to these troubling safety concerns, the development of transmissible vaccines will incur grave biosecurity risks due to the dual-use potential of the insights, tools and experience gained through such work.

First, transmissible vaccine research will create an incentive to explore ways of engineering viral vectors to evade the immune response, as any pre-existing immunity to the vaccine vector will slow vaccine spread. While the authors propose that choosing a vector with propensity for superinfection or little pre-existing immunity might be sufficient to circumvent this issue, the efficacy of these vectors could also be improved through immune evasion. In contrast to investigators developing gene therapy modalities, who can explore one-time chemical modifications to overcome immune responses, transmissible vaccines would require heritable approaches also applicable to infectious, potentially pandemic agents. Second, research on candidate transmissible vectors would uniquely focus on engineering and testing both transmissibility and genomic stability, traits which might be directly translated to viruses capable of infecting humans. Viral vectors optimized for these properties could be directly repurposed to deliberately cause harm6.

The history of biological weapons programmes suggests that such dual-use applications are not merely hypothetical: the Soviet Biopreparat programme reportedly sought to increase the transmissibility and virulence of smallpox, and the known attempts of groups such as Aum Shinrikyo to obtain deadly pathogens and engineer weapons of mass destruction underscores that potential misuse of these comparatively accessible biotechnologies would not be limited to state actors7,8.

Recommendation for transferable vaccines

In contrast to the abundance of highly concerning and unpredictable risks associated with the development of transmissible vaccines, we agree with Nuismer and Bull that risks associated with transferable vaccines are better understood and seem to be similar to those of widespread distribution of vaccine-laced bait. While there is a disadvantage associated with the finite number of transmissions of transferable vaccines, Bull and colleagues9 find that this disadvantage is small. Furthermore, a promising proof-of-concept study in vampire bats suggests that transferable vaccines might be within reach10. We consequently urge future developers of self-disseminating vaccination approaches to explore the creation and optimization of transferable vaccines.