Perhaps no zoonotic disease represents the potential successes—and challenges—of preventing zoonotic disease transmission to humans such as rabies. Without appropriate vaccination, rabies is an invariably fatal, acute encephalitic disease caused by viruses of the Lyssavirus genus which is responsible for an estimated 59,000 human deaths annually ^[1][14]. Globally, the rabies virus variant that circulates in dogs presents the most serious public health threat among Lyssaviruses and is responsible for up to 99% of human deaths, mostly in children ^[1][14]. In the United States, human rabies cases declined precipitously following the implementation of canine vaccination regulations in the 1940s, and canine rabies was declared eliminated in 2007 ^[2][13]. However, the vaccination of dogs is still considered a high priority because Rabies virus variants are still present in several terrestrial meso-carnivore and bat species, and spillover from wildlife continues to pose an ongoing public health risk to humans, domestic dogs, and other animals in the United States.

Rabies management with oral rabies vaccination (ORV) has been successfully demonstrated with coyotes, gray fox, and raccoons, while canine rabies vaccination in the United States utilizes a parenteral (injection) approach. Ecological models and empirical evidence support that the vaccination coverage of at least 70% of free-roaming dog populations can eliminate the circulation of canine variants of rabies if maintained for a minimum of five years. A recent global analysis estimated that it would cost approximately USD 6.3 billion to eliminate canine rabies worldwide by 2030 through mass dog vaccination; this investment would prevent an estimated 500,000 human rabies deaths over the next 20 years ^[3][32]. However, meeting this ambitious goal would require a dramatic acceleration of funding and resource prioritization.

The oral vaccination of dogs using live-attenuated viruses has gained attention as a new tool to advance dog-mediated rabies elimination ^[4][33]. This is a particularly attractive option for parts of the world where free-roaming dogs are challenging to catch and handle for parenteral vaccination. However, unfounded concerns regarding the safety and efficacy of well-studied ORV may delay large-scale implementation. The large-scale use of ORV for wildlife--which lacks motivation for use in dogs—presents a paradox for the rabies community. While further study and awareness campaigns to improve community acceptance may eventually enable the effective use of ORV for dogs, delays in the adoption of effective tools such as ORV enable the continued persistence of the rabies virus in dogs around the world and perpetuates otherwise preventable human deaths in many countries.

Despite the fact that vaccines for humans and animals have existed since 1885 and 1921, respectively, the rabies virus continues to cost an estimated USD 8.6 B USD per year globally ^[1][5][6][14,34,35]. Overall, 55% of the primary global economic burden of rabies is due to premature death, while 20% is attributed to post-exposure prophylaxis (PEP) use. Thus, preventing human deaths is a highly cost-effective strategy compared to the estimated cost of global elimination ^[1][14]. However, few countries in the past decade have made major advances in the elimination of the canine variant and the United States has not yet achieved the focal elimination of its most significant wildlife strain of rabies, namely the raccoon variant. Adequate funding, improvements in vaccine accessibility, and the inclusion of live-attenuated rabies viruses for oral vaccination are important tools that would help to see these goals achieved.

Brucellosis is one the most common zoonotic diseases globally, impacting many species of animals, and is an example of both the opportunities and challenges of vaccine implementation. It also illustrates how in a contemporary vaccine prevention program, even highly successful efforts must evolve and modernize to address the changing disease landscape.

Historically, in the United States, Brucella abortus infections in cattle caused devastating chronic illness in people and significant economic losses in livestock due to abortions and fetal loss ^[7][36]. Animal vaccine programs were developed by the agriculture sectors to prevent agricultural losses and to protect human health by reducing the risk of zoonotic transmission. The US Brucellosis Eradication Program, established in 1934 and implemented by states through a complex set of laws and regulatory programs, exemplifies how successfully controlling the disease in cattle population has a direct impact on reducing the number of reported cases of human brucellosis ^[8][37].

Presently, brucellosis cases in humans are rarely reported in the United States and occur mainly in immigrants and travelers who are exposed to the disease outside of the United States ^[9][10][16,38]. Brucella abortus infection has been successfully eliminated from United States cattle herds as a result of this important program. The only remaining risk in the United States remains near Yellowstone National Park, associated with the possible spillover from bison and elk herds that were originally infected by cattle ^[11][39]. Additionally, vigilance is still required on the US–Mexico border to monitor for geographic expansion from that enzootic region. Despite the success of the eradication program and resulting negligible human risk of exposure throughout most of the United States, large numbers of cattle continue to receive modified live Brucella abortus vaccines in the United States today as directed by regulatory processes that were established to support the US Brucellosis Eradication Program ^[7][36].

Notably, an emerging risk factor for human brucellosis in the United States is the vaccine itself. Three live attenuated vaccines to prevent two Brucella species (B. abortus and B. melitensis) in animals are commercially available ^[12][13][40,41]. While less pathogenic than wild-type Brucella species, all three vaccines are pathogenic in humans and can cause clinical illness. Currently, the B. abortus vaccine RB51 is actively used throughout the United States, and it was considered less pathogenic (and therefore safer to humans) than the prior historic vaccine Strain 19 ^[14][42]. Over time, the use of the Brucella vaccine, as well as the rapid identification of animals and removal from affected herds, contributed to the United States’ highly successful elimination of Brucella from US cattle herds ^[7][36]. With its widespread use, however, accidental exposures to the vaccine, such as veterinarian exposures to RB51 through needlestick injury, continue to occur. ^[15][16][17][43,44,45].

An emerging public health risk of concern from RB51 has been identified and is associated with a rise in popularity among the general public of consuming unpasteurized (raw) milk and milk products within the United States. This has resulted, in part, from changes in laws permitting raw milk sales in retail stores or directly to consumers in over half of US states ^[18][46]. As a result, RB51 cases have been recently diagnosed in people who consume unpasteurized dairy products obtained from previously vaccinated animals ^[9][19][20][16,17,47]. In this setting, some small percentage of cows that are vaccinated in calfhood as part of state and federal programs never clear the vaccine strain and develop a chronic infection, shedding infectious bacteria in milk during later lactation stages ^[7][21][36,48]. Several recent human cases of RB51 linked to raw milk have been reported, and in the United States, the general public is at higher risk of RB51 than wild-type infection, especially when consumer preferences remove protective pasteurization processes from milk and dairy products ^[9][19][16,17]. Currently, the legislation related raw milk is enacted at a state level, and interstate sales are illegal ^[18][46]. For recent cases of RB51 among humans in the United States, both implicated cows were Jersey breeds, and the chronic shedding of RB51 post-vaccination is believed to be more common in some individual animals of Jersey breed ^[19][20][17,47].

An initial risk assessment of the RB51 vaccine was performed to evaluate the impact of the vaccine on the safety of animals, public health, and the environment ^[22][49]. The USDA Animal and Plant Health Inspection Service (APHIS) also conducted an environmental assessment and concluded that the licensure of RB51 would not significantly affect the quality of the human environment ^[22][49]. However, the safety assessment was conducted during the time when farmers and veterinarians were populations at the greatest risk of exposure to RB51 from accidental vaccine sticks, and before the rise in popularity of consuming raw milk and milk products among the general public in the United States. The assessment was also conducted to ascertain safety compared to the older Brucella vaccine Strain 19, which was more highly pathogenic to humans and livestock. The changes in the environmental risk of exposure to Brucella in the United States, as well as the changing demographics of at-risk populations, represent an expanding gap that has developed since the original vaccine assessments were performed.

RB51 was developed as a vaccine that could differentiate infected from vaccinated animals (DIVA), an important tool for surveillance purposes. However, because traditional serologic methods to detect brucellosis were not designed to identify RB51 in either humans or animals, and symptoms can be non-specific and wax and wane, human cases are undoubtedly underdiagnosed and underreported ^[16][23][44,50]. Additionally, RB51 is resistant to rifampin and penicillin, which are the first-line medications used to treat human brucellosis, further complicating human treatment and diagnosis ^[16][24][44,51]. While the CDC established a passive surveillance system from 1998 to 1999 to identify cases of accidental RB51 exposure among veterinarians and farmers, this system did not evaluate possible RB51 infection from exposure to unpasteurized dairy products ^[17][45]. National surveillance for human Brucella infections is tracked through the CDC’s National Notifiable Diseases Surveillance System (NNDSS), and brucellosis cases are commonly investigated by state health authorities to assess possible sources of domestic or international exposure ^[25][52]. However, because it is so challenging to detect human infections with RB51, which may be milder than traditional cases of brucellosis, it is uncertain whether current surveillance practices are sufficient for detection and reporting through the NNDSS, and unclear how widespread the human RB51 infection caused by raw milk consumption may be. This gap may become increasingly problematic as consumer preferences continue to evolve ^[17][26][45,53]. Further developments to enhance vaccine safety to produce non-pathogenic animal vaccine strains should be considered an important future research horizon if the consumption of unpasteurized dairy products becomes more widespread in the United States. Additionally, changes in vaccine program administration in the context of emerging human health risks should be discussed collaboratively between the public health and agriculture sectors. For example, implementing screening programs on raw milk dairies and antigen-based tests could provide targeted testing to help protect public health. Similarly, the current state requirements for Brucella vaccination programs could be re-examined, particularly for the cows used for raw milk dairies and in breeds at risk for chronic shedding.

Nothing illustrates the potential perils of zoonotic disease risks as dramatically as the COVID-19 pandemic. Coronaviruses include several known zoonotic pathogens, most notably the Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 1 and 2 (SARS-CoV-1 and SARS-CoV-2). These viral pathogens highlight the challenges and opportunities for vaccine use to prevent emerging zoonotic transmission, and the necessity of taking a flexible and adaptive approach. MERS-CoV is a relatively rare zoonotic infection with epidemic potential that has caused severe respiratory illness in people. Multiple lines of evidence point to dromedary camels as a reservoir host ^{[27][28][29][30]}[54,55,56,57]. Three potential vaccination strategies to prevent MERS-CoV infection are currently under consideration: (1) the vaccination of camels to prevent the camel-to-human transmission of MERS-CoV; (2) the vaccination of specific at-risk human populations (e.g., healthcare personnel and those with occupational exposure to camels); and (3) the reactive use of a vaccine in at-risk humans as a means of outbreak control. Camel vaccination would likely provide minimal benefit to the animals ^[31][58], but given the severity of disease in humans, the lack of viable treatment options, and epidemic potential, camel vaccination is still considered a viable preventive measure for human infection. Vaccine trials for MERS-CoV are underway in both camels ^[32][33][59,60] and humans ^[34][35][61,62], with one candidate, the ChAdOx1 MERS CoV vaccine, undergoing trials across both camels and humans ^[32][35][59,62].

In contrast, SARS-CoV-2, the virus that causes COVID-19, while suspected to have originated in an animal reservoir, has reached pandemic levels through sustained person-to-person transmission. Additionally, transmission from humans to a wide range of mammalian animals has been documented, including companion animals (dogs, cats, and ferrets), exotic animals (lions, tigers, and other large cats, non-human primates, otters, and multiple other species), production animals such as farmed mink, and most recently, free-ranging white-tailed deer, and additional susceptible animal species continue to be identified ^[36][37][63,64]. At the time of publishing, the Pfizer-BioNTech COVID-19 Vaccine and Moderna Spikevax vaccines have been approved by the FDA for use in humans, and the Johnson & Johnson has been approved under emergency use authorization (EUA) in the United States ^[38][39][65,66]. An experimental animal vaccine developed by Zoetis has been authorized for use in mink herds and zoo animals that have demonstrated natural susceptibility to SARS-CoV-2 infection ^[40][67]. Given the potential for the zoonotic transmission of SARS-CoV-2 from mink to humans, in addition to the emergence of novel viral variants in this animal species documented in Europe ^[41][68], vaccinating mink as a mechanism to protect both animal and human health has been implemented in the United States. This initiative has, in part, been fueled by concerns about vaccine and therapeutic efficacy in the context of mink-associated viral variants which resulted in the mass culling of the mink population in Denmark ^[41][68].

While the vaccination of people primarily serves to protect them against illness and death, it has the indirect benefit of potentially preventing zoonotic transmission from people to animals. Prior reports have documented the transmission of SARS-CoV-2 from humans to critically endangered and valuable zoo animal species ^[42][69]. Experimental animal vaccines have been used to protect these species from disease transmission from humans ^[43][70]. The finding of widespread SARS-CoV-2 transmission among white-tailed deer in the United States and Canada following the likely spread from people has raised concerns about whether the virus might become enzootic in this species, which could lead to further viral evolution and the emergence of new mutations or variants with public health impacts ^[36][44][63,71]. Further research is needed to better elucidate any indirect protection that vaccinating people may provide to animals. Preventing inter-species transmission from people to animals and among animals, which may in part be accomplished by vaccinating humans, could reduce the emergence of variants and help preserve vaccine efficacy. SARS-CoV-2 demonstrates the complexities of inter-species disease transmission, further highlighting how prevention and control efforts such as vaccination should reflect the shared threat of disease among humans and a variety of animal species.

For influenza viruses, human and animal vaccines play critical roles in protecting the individual, preventing zoonotic transmission, and preventing virus reassortment (i.e., recombining larger gene segments from different viruses) that may lead to a novel virus with pandemic potential. In addition to humans, influenza A viruses are known to routinely circulate in six animal species or groups (i.e., wild water birds, domestic poultry, swine, horses, dogs, and bats), and can infect many other animal species through inter-species transmission ^[45][46][1,2].

Influenza A viruses are constantly evolving, making it possible on rare occasions for animal influenza viruses to change in such a way that they can easily infect people ^[47][48][3,4]. As with SARS-CoV-2, influenza vaccines not only directly protect the recipient, but also prevent inter-species transmission, which can facilitate the emergence of new viruses ^[45][49][1,5].

Many influenza A viruses are not host specific; for instance, humans and some animals, such as pigs and dogs, can be infected with either swine, human, or avian influenza viruses. If a host is infected with different viruses at the same time, it is possible for reassortment to occur and create a novel virus. While it is unusual, sporadic human infections caused by certain avian influenza viruses and swine influenza viruses have been reported. In combination with other measures, vaccines are a valuable tool in preventing the zoonotic transmission of influenza viruses.

In the United States, in addition to seasonal influenza vaccines for humans, there are 12 animal influenza vaccines licensed through the United States Department of Agriculture’s Center for Veterinary Biologics (USDA CVB). Vaccines are available for domestic poultry (3), swine (5), horses (1), and dogs (3), in function of the needs of the individual animal owners, whether they be commercial animal production facilities, family agriculture farms, or companion animal owners ^[50][6]. Swine are vaccinated, while birds are not, and the lack of an oral vaccine for the mass vaccination of poultry presents a challenge for the poultry industry. To be most effective, it is important for the animal influenza vaccines to antigenically match the influenza virus strain currently circulating in the respective animal species.

A candidate vaccine virus (CVV) is an influenza virus that has been prepared by the Centers for Disease Control and Prevention (CDC)—or another public health agency—that can be used by vaccine manufacturers to produce an influenza vaccine for humans ^[51][7]. In addition to preparing CVVs for human seasonal influenza vaccine production, the CDC routinely develops CVVs for novel avian and swine influenza viruses with pandemic potential as part of their pandemic preparedness activities ^[52][8]. Influenza vaccines protect against specific influenza viruses, with minimal cross protection against other influenza viruses, so the first step in creating a CVV against a particular avian or swine influenza virus is to identify the emerging animal influenza virus that is posing or may pose a risk to human health ^[52][53][54][8,9,10].

The tendency of influenza A viruses for mutation and reassortment, combined with the presence of wildlife reservoirs, the circulation of avian influenza viruses in domestic poultry, and the diversity of swine influenza viruses in the domestic swine population, make vaccine development a challenge. However, influenza vaccination in animals remains an important measure to control and prevent reassortment events and zoonotic transmission, and to reduce influenza illness in humans and animals.