Orthopoxvirus reservoirs have become increasingly important to public health since smallpox was declared eradicated in 1980. That global achievement was made possible through intensive vaccination, surveillance and containment, aided by the fact that variola virus had no nonhuman animal reservoir capable of sustaining transmission. After eradication, routine smallpox vaccination largely ended, gradually reducing the population-level immunity that had also provided protection against related orthopoxviruses. This decline has left more people susceptible as zoonotic viruses such as mpox and borealpox continue circulating or emerging from animal hosts.

Today, Orthopoxviruses remain a diverse group, circulating in various animal reservoirs. Their ability to periodically emerge in humans presents a complex challenge for public health interventions. Recent developments, such as the global spread of mpox virus and the emergence of the novel borealpox virus from an unknown animal reservoir, highlight the ongoing threat posed by these viruses.

Orthopoxviruses are notable for their varied host breadth and pathogenicity in mammals. While the full extent of their circulation in wildlife is not entirely understood, this diversity in host range is partly attributed to accessory genes within their viral genomes. These genes can influence how the virus interacts with a host’s immune responses.

The evolutionary path of OPVs involves gains and losses of these accessory genes. Genome reduction, for instance, is thought to contribute to host specialization. For example, the modified vaccinia virus Ankara, a smallpox vaccine, lost a significant portion of its genetic information. This loss included many genes used by OPVs to regulate the mammalian host environment, resulting in a restricted host range.

Conversely, other OPVs, such as mpox virus (formerly monkeypox virus) and cowpox virus, can infect a broad spectrum of hosts. This broad host range increases the likelihood of recurrent spillover events into human populations. The recent global spread of mpox, in particular, has raised concerns about the potential for human-to-animal spillback. This phenomenon could see the virus transmitted to susceptible animal hosts outside its known historical range.

Host spillover is the cross-species transmission of a virus from its usual reservoir host into a different species. This event can lead to infection that may or may not continue spreading in the new host. It acts as the decisive starting point for many viral outbreaks, regardless of their scale. An estimated 60 to 75 percent of human infectious diseases have originated through such spillover events. These events pose significant threats across both animal and plant kingdoms.

The emergence of borealpox virus in humans from an unidentified animal reservoir further underscores the likelihood of unknown OPVs existing in nature with zoonotic potential. Zoonotic potential refers to the capacity of a virus to transmit from animals to humans. Identifying the possible animal reservoir hosts for these viruses is a critical step in mitigating future outbreaks.

Understanding the specific genomic features that predict which animal species can act as reservoirs for Orthopoxviruses is essential. This knowledge can inform targeted surveillance efforts and help develop strategies to prevent future zoonotic spillover events. The ongoing research into these viral genomic features is vital for protecting public health against emerging and re-emerging viral threats.

The Legacy of Smallpox Eradication

The successful eradication of smallpox in 1980 marked a monumental achievement in global public health. This success was uniquely tied to the variola virus’s inability to survive outside human populations, making global vaccination efforts highly effective. After this triumph, widespread smallpox vaccinations were largely discontinued across the world. This decision, while logical at the time, resulted in a significant reduction in collective immunological memory against the broader Orthopoxvirus genus.

This reduced immunity means that human populations are now more susceptible to other OPVs that continue to circulate in animal reservoirs. The historical context of smallpox eradication highlights a critical difference. Most other OPVs do possess animal hosts, complicating intervention efforts and creating a persistent risk of zoonotic transmission.

Orthopoxvirus Diversity and Host Range

The Orthopoxvirus genus encompasses a diverse array of viruses, each with varying host breadth and pathogenicity. Their ability to infect a wide range of mammalian hosts is influenced by a large repertoire of accessory genes. These genes are involved in inhibiting host innate immune responses, allowing the viruses to adapt to different mammalian environments.

The evolutionary dynamics of OPVs often involve the gain or loss of these accessory genes. For example, the modified vaccinia virus Ankara lost about 15% of its genome, including genes crucial for regulating the host environment. This genetic reduction led to a significantly restricted host range. In contrast, viruses like mpox and cowpox maintain broader host ranges, making them more prone to cross-species transmission.

Understanding Host Spillover Risk

Host spillover occurs when a virus moves from its natural reservoir host to a new species. This phenomenon is a primary cause of many viral outbreaks, affecting both animal and plant kingdoms. Approximately 60 to 75 percent of human infectious diseases, including recent pandemics, began with such an event. Understanding the mechanisms behind spillover is crucial for preventing future outbreaks.

The widespread impact of these outbreaks can lead to cascading consequences for human health, food security, and economic stability. While research efforts disproportionately focus on human pathogens, the escalating risk of pandemics in both animal and plant systems demands a comprehensive approach. Prioritizing the protection of critical food grains, for example, is vital for sustaining the world’s growing population.

The Challenge of Unidentified Reservoirs

The recent emergence of the novel borealpox virus in humans from an unknown animal reservoir highlights a significant gap in our understanding. This event suggests that there are likely many unidentified Orthopoxviruses in nature with the potential to jump to human populations. The global spread of mpox has also raised concerns about human-to-animal spillback, similar to what was observed with SARS-CoV-2 in white-tailed deer.

Identifying these hidden animal reservoirs is a complex but essential task. It involves detailed genomic analysis to predict host species and ongoing surveillance in wildlife populations. Such efforts are fundamental to developing effective public health strategies and preventing the next major viral outbreak.