Benefit risk considerations for African swine fever virus live attenuated vaccines

Abstract

In response to the recent publication on safety concerns related to “ASFV-G-∆I177L” by van den Born et al. (2025), we emphasize the need for a thorough, context-specific risk assessment before drawing conclusions about the general field use of the ASFV-G-∆I177L vaccine strain. While valid safety concerns were raised, historical precedents highlight that potential risks, including reversion or recombination, can be managed effectively within structured vaccination strategies.

In response to the recent publication by van den Born et al., this comment addresses the potential impact of the observed genetic changes in the modified live ASFV-G-∆I177L vaccine strain, which regained virulence after forced animal passages and showed adverse effects in pregnant sows. While the authors caution against its use in field control, we emphasize the importance of a thorough evaluation of the risks and benefits. Drawing from historical precedents of similar vaccines, we suggest that context-specific decisions, along with further transmission studies and risk assessments, are essential before making definitive conclusions.

Van den Born et al. recently observed that the modified live ASFV-G-∆I177L vaccine strain¹ can undergo genetic changes when subjected to forced animal passages². Such passages are essential for reversion studies on virulence, which assess the genetic stability of vaccine viruses (VICH Guideline 41). During these passages, ASFV-G-∆I177L regained replication competence and exhibited renewed pathogenic properties. The authors conclude that ASFV-G-∆I177L should not be used for ASF control measures in the field.

While we recognize the importance of these findings, we emphasize the need for careful consideration before outright acceptance or rejection for all conditions.

Ideally, a vaccine should not pose a risk of reversion or recombination. However, to date, only live-attenuated vaccines have demonstrated efficacy against ASF, and such vaccines, like field strains, inherently retain the ability to evolve during replication. This phenomenon has now been observed for ASFV-G-∆I177L and previously for ASFV-G-∆MGF³. In veterinary medicine, there are precedents of vaccines that exhibited increased virulence during forced passages or recombined with field viruses, yet were successfully and safely deployed in controlled vaccination campaigns. One example is the live-attenuated GPE−strain against Classical Swine Fever (CSF). This vaccine strain was derived from the virulent ALD strain through serial passages in pig, cattle, and guinea pig cells. Subsequent in vivo back-passages led to increased virulence, characterized by prolonged viremia and clinical signs of CSF⁴. Despite this, the vaccine remains in use in the field⁵ with no significant safety concerns. The design of the vaccination strategy, i.e., restriction to fattening pigs, implementation of targeted surveillance, and optimization of herd management and biosecurity were key factors to limit and mitigate potential risks. Under intensive field use in Asia, the vaccine strain produced rarely viraemia or shedding. Another example is large-scale vaccination with gE-deleted modified live vaccines against Aujesky’s Disease or bovine herpesvirus type 1 infection (BoHV-1), where the recombination potential between vaccine and field viruses has been documented for both^6–8. However, this did not affect the effectiveness of the vaccination program when implemented within a well-structured strategy⁹. Using gE-deleted herpesvirus vaccines on millions of farm animals has been extremely successful. The recombination possibilities and theoretical safety issues observed in experiments were not relevant in practice. Once again, surveillance and herd management—for example, the removal of reactors—were important factors in the ultimate success.

It is important to consider that classical studies on the efficacy and safety of ASFV-G-∆I177L in target species have yielded promising results, with controlled field trials demonstrating favorable outcomes in fattening pigs. Reversion-to-virulence passages represent highly artificial conditions, imposing strict bottlenecks that do not fully reflect real-world epidemiological dynamics. Nonetheless, they provide valuable insights into viral evolution under worst-case scenarios. In our opinion, a fact-based benefit-risk assessment is essential to determine whether the advantages of a vaccine outweigh its potential risks in specific contexts. The balance of the benefit-risk assessment may differ depending on the local epidemiological, regulatory, and production conditions.

While increased virulence would be concerning for prophylactic vaccination, the associated risks may be more acceptable in emergency scenarios, particularly if a highly virulent field strain is already circulating and threatening to spread uncontrollably or the field strains involved show diversification of clinical outcomes. Given that field strains can cause mortality rates approaching 100%¹⁰, it is unlikely that a vaccine strain would exceed this level of virulence. However, it is critical to prevent the emergence of strains with milder clinical signs but enhanced transmissibility or a propensity for chronic disease, as observed in Spain and Portugal⁴. Those strains would significantly complicate disease control efforts. Comprehensive research is needed to evaluate these issues of vaccine stability.

The authors also report on safety concerns for pregnant animals. In detail, vaccination in late pregnancy led to clinical disease in both sows and their offspring. This problem could potentially be circumvented by either not vaccinating breeding stock or vaccinating sows prior to mating/insemination. However, further experimental studies are necessary to fully assess the safety of ASFV-G-∆I177L or other live-attenuated vaccines and the effectiveness of potential countermeasures in these settings. These studies have to align with the recently adopted WOAH guidelines for ASF vaccines.

In our opinion, key aspects in evaluating an ASF vaccine include viral transmissibility and disease progression. A comprehensive analysis of these factors is essential to make an informed decision regarding its application in disease control strategies. Should upcoming transmission studies show that a revertant of ASFV-G-∆I177L with increased virulence is detected in an animal, but not shed and therefore unlikely transmitted to other pigs, a comprehensive risk assessment could conclude that using ASFV-G-∆I177L in the field is still beneficial. In case transmissibility is increased, there is good reason to caution against the use of the vaccine. To answer these relevant and current questions promptly, transmission experiments are already planned.

Concluding, it is of crucial importance not to make hasty decisions, neither for acceptance nor for premature rejections. Additional studies are needed to feed into epidemiological modeling and potential strategy design. Potential vaccination strategies may differ among outbreak scenarios and world regions.

Author contributions

S.B., V.F., A.S. and M.B. wrote, revised, and edited the manuscript. All authors approve of the submitted manuscript.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

S.B., V.F., A.S., and M.B. work on the EU-funded project ASFaVIP (African Swine Fever attenuated live Vaccines In Pigs), investigating, among others, the vaccine candidate ASFV-G-ΔI177L as a potential live-attenuated vaccine for the European market. None of the authors has a direct financial interest in the candidate ASFV-G-ΔI177L.