Severe acute respiratory syndrome (SARS) CoV-2 is the causative agent of the COVID-19 pandemic that began in 2019. At the time of writing, there is debate as to whether COVID-19 ought to be classified as a zoonotic disease or an emerging infectious disease with probable animal origin.1 In any case, animal reservoirs are strongly suspected and reverse zoonosis, the transmission of the virus from humans to animals, has been documented.2–5 Human-animal interfaces must be considered when exploring the epidemiology of this important pathogen, including the interactions that humans have with livestock, pets, and in zoological settings. The close proximity of species in a zoo setting that would be unlikely in a natural setting provides ample opportunities for pathogen cross-transmission between animals of different taxonomic groupings. Further, some guest experiences (eg, petting zoos and giraffe feeding stations) allow close contact between patrons and collection animals. Zoo collection animals from a diverse range of taxon groups, including nondomestic felids (lions, tigers, snow leopards, fishing cat, cougar, and lynx), nonhuman primates, and other mammals (otters, hyenas, hippopotamuses, manatees, coatimundi, and binturong) have tested positive for COVID-19.6 Positive animals either were asymptomatic or displayed mostly respiratory clinical signs, ranging from mild illness with short duration to more severe cases requiring extensive care. Some severe cases resulted in death.7 Consistency of the structure of the spike protein, the SARS-CoV-2 cellular binding receptor, across 410 vertebrate species suggests that the virus has a broad host range, underscoring the breadth of impact that this virus can and may have worldwide.8
The role of small ruminants is important to consider when investigating the epidemiology of COVID-19 because they have varied and close interactions with humans as livestock, companion animals, and zoo collection animals. Antibodies to SARS-CoV-2 were detected in 40% of white-tailed deer, demonstrating substantial viral exposure in wild ruminants.3 Deer in Michigan were reported to have the highest antibody prevalence (67%) relative to deer in adjacent states, suggesting a high level of exposure.9 Between April 2020 and December 2020, 33.2% of sampled free-living and captive deer in Iowa were reported PCR positive for SARS-CoV-2 RNA. Between November 2020 and January 2021, 82.5% of the samples were PCR positive.10 Additionally, white-tailed deer in New York City were found to be infected with Delta and Omicron variants coinciding with the waves of infection in humans.10
There is conflicting data as to whether ruminants can sustain replication of the virus. An ex vivo study demonstrated that cattle and sheep sustain viral replication of SARS-CoV-2, suggesting that ruminants could serve as potential reservoirs of the virus.4 However, an in vivo study that inoculated 6 colostrum-deprived Holstein calves detected SARS-CoV-2 RNA in only 2 nasal swabs at any timepoint postinoculation.11 Infectious virus was not detected in these swabs, which suggested there was no replication of the virus in these animals.11 Another study that inoculated 6 calves also detected SARS-CoV-2 RNA in only 2 nasal swabs.5 These investigators re-introduced the inoculated calves to naïve calves and the naïve calves did not become infected with SARS-CoV-2.5 An experimental study in white-tailed deer fawns, however, demonstrated SARS-CoV-2 shedding in nasal secretions and transmission to other deer.12 A study of the deer outbreak in Ontario, Canada also demonstrated potential deer-to-human transmission.13 These results provide justification for further research into the potential role of various ruminants in COVID-19 epidemiology and suggest that prevention strategies should be explored in these species.
Zoetis has developed a vaccine using recombinant S protein technology in which a highly purified, soluble, recombinant SARS-CoV-2 Wuhan-1 spike ectodomain protein is formulated with a proprietary, aqueous adjuvant system that contains an immunomodulator (Mink Coronavirus Vaccine, Subunit; Zoetis, Inc)14 The trimeric spike protein is stabilized in the prefusion conformation and has been demonstrated to cross-neutralize Alpha and Delta variants.15 The experimental vaccine was provided to zoological facilities for experimental use in species deemed at risk of contracting disease. Doses were administered after approval by the United States Department of Agriculture Center for Veterinary Biologics on a case-by-case basis. Subsequent to this study, the vaccine had received a conditional license in the United States for use in mink. The vaccine is now known as the Mink Coronavirus Vaccine, Subunit. The vaccine is labeled for SC administration with a 3 week interval between the initial vaccine and second dose.14 At the time of this publication, there was no published information pertaining to safety nor efficacy of this vaccine in ruminants.
The purpose of this study was to determine the antibody titers of caprids to COVID-19 after 2 doses of the Zoetis SARS-CoV-2 vaccine using routes of administration frequently implemented in zoological medicine settings (SC and IM). Neutralizing antibody titers were measured before vaccination to assess for prior subclinical exposure to the virus and up to 6 months after the first vaccine dose.
Methods
Animals
Thirty-one domestic goats in public contact yards from 4 different zoological institutions in Michigan, which were accredited by the Association of Zoos and Aquariums (AZA), were enrolled in this study. All were deemed clinically healthy at the start of the study based on physical exam and bloodwork (CBC, fibrinogen, and biochemistry panel). Goats were housed in social groups with indoor and outdoor access. Diets varied by institution but generally included grass hay and fresh water ad libitum with access to a mineral block; some goats were fed prescribed amounts of pelleted feed. This study was approved by the Institutional Animal Care and Use Committee at the Binder Park Zoo and research committees at Potter Park Zoo, Saginaw Children's Zoo, and John Ball Zoo.
Experimental design
The study took place between September 27, 2021, and June 01, 2022. Goats were manually restrained for procedures. Each goat was administered 1 mL Zoetis SARS-CoV-2 vaccine SC over the biceps femoris muscle at 3 institutions (n = 22) or IM in the biceps femoris muscle at 1 institution (n = 9) based on the preference of the administering veterinarian. A second dose was administered 21 (SC) or 28 (IM) days after the initial vaccine in the same anatomic location. Administration of the second dose was delayed for 1-week at the institution administering vaccines IM due to a human COVID outbreak at that institution. The COVID outbreak caused staffing disturbances that precluded dedicating personnel resources to the study, but the staff members known to be infected with COVID did not come in contact with the goats during the infective window.
Blood samples (6 mL) were obtained from the jugular vein at the following time points relative to vaccination (the day of initial vaccination is referred to as day 0): immediately before the initial vaccination (day 0) and at 21- (SC only), 28- (IM only), 42-, 90-, and 180-days postvaccination. The blood was placed into serum separator tubes and allowed to clot. Serum was separated within 1 hour of collection via centrifugation for 10 minutes at 2,000 X g, and serum supernatant was harvested and stored in cryogenic vials in an ultralow freezer (−80 °C) until analysis.
Viral serum neutralization assay
Seroconversion to SARS-CoV-2 was assessed by a virus neutralization assay (VN; Cornell AHDC).16 Two-fold serial dilutions (1:8 to 1:4,096) of serum samples were incubated with 100 50% tissue culture infective doses (TCID50) of SARS-CoV-2 isolate Tiger 1 (D614G)16 on Vero cells for 1 h at 37 °C. After incubation of serum and virus, 50μL of a cell suspension of Vero C1008 (Vero 76, clone E6, and Vero E6) (ATCC® CRL-1586™) cells was added to each well of a 96-well plate and incubated for 72 h at 37 °C with 5% CO2. The virus cytopathic effect (CPE) was used as an indicator of virus infection/replication. Neutralizing antibody titers were expressed as the reciprocal of the highest dilution of serum that completely inhibited CPE. Appropriate positive and negative control sera were included, and all samples were tested in duplicate. A cell culture control was included in the assays, and the virus working dilution was back-titrated.
Statistical analysis
The distributions of serum titers by route and day were assessed for normality via the Shapiro-Wilks test. The majority were not normally distributed and the data were log transformed by base 10 for statistical analysis; P < .05 was considered statistically significant. A mixed-model ANOVA was performed with route (SC and IM) and repeated measures of titers at days 0, 21/28, 42, 90, and 180 and then was followed by Tukey's test for multiple comparisons. Chi-square or Fisher's exact test was used to compare the proportion of goats with a positive titer at each time point (day 0, day 21 vs 28, day 42, day 90, and day 180) between the 2 routes of administration groups (IM vs SC). All statistical analysis was performed with standard software (JMP Pro 16; JMP Statistical Discovery LLC).17
Results
Twenty male and 11 female goats were enrolled in the study; the median age was 10 years, range = 7–15 years; the median weight was 43.5 kg, range = 22–110 kg. Subspecies of goat included African pygmy (n = 16), American pygmy (n = 4), domestic (n = 1), Kinder (n = 2), Nubian (n = 2), and San Clemente Island (n = 6).
Before vaccination (day 0), none of the goats had detectable antibodies to SARS-CoV-2 at a 1:8 dilution. On day 21, 68% of the goats vaccinated SC had detectable serum titers, but on day 28, 0% of the IM-vaccinated goats had detectable titers (Tables 1 and 2). There was no statistically significant difference between the proportion of goats with positive serum titers between SC and IM groups on day 42 or 90 (P > .05). However, there was a statistically significant difference between the proportion of goats with detectable titers when comparing day 21 (SC) vs 28 (IM) (P < .001) and between groups on day 180 (P < .05; Table 3).
Biological information and antibody titers at designated time points relative to vaccination detected by virus neutralization in 31 domestic goats (Capra hircus) that received 1 mL of vaccine against SARS-COV-2 (Mink Coronavirus Vaccine, Subunit; Zoetis).
| Antibody titers | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Goat | Species | Sex | Age (y) | Weight (kg) | Vaccine administration route | Day 0 | Day 21 | Day 28 | Day 42 | Day 90 | Day 180 |
| 1 | African pygmy | M | 7 | 43.5 | SC | 0 | 64 | — | 128 | 32 | 32 |
| 2 | Domestic | M | 8 | 60.5 | SC | 0 | 8 | — | 128 | 32 | 0 |
| 3 | San Clemente Island | M | 7 | 63.6 | SC | 0 | 16 | — | 128 | 32 | 8 |
| 4 | San Clemente Island | F | 7 | 46.0 | SC | 0 | 16 | — | 128 | 32 | 0 |
| 5 | San Clemente Island | F | 7 | 38.0 | SC | 0 | 32 | — | 2048 | 128 | 32 |
| 6 | San Clemente Island | F | 7 | 37.6 | SC | 0 | 16 | — | 128 | 64 | 8 |
| 7 | San Clemente Island | F | 7 | 39.8 | SC | 0 | 16 | — | 512 | 128 | 32 |
| 8 | San Clemente Island | F | 7 | 45.0 | SC | 0 | 8 | — | 256 | 32 | 16 |
| 9 | African pygmy | M | 10 | 33.0 | IM | 0 | — | 0 | 2048 | 256 | 64 |
| 10 | African pygmy | M | 10 | 32.4 | IM | 0 | — | 0 | 1024 | 128 | 32 |
| 11 | African pygmy | M | 11 | 41.4 | IM | 0 | — | 0 | 256 | 32 | 16 |
| 12 | African pygmy | M | 11 | 40.8 | IM | 0 | — | 0 | 1024 | 64 | 32 |
| 13 | African pygmy | M | 10 | 45.1 | IM | 0 | — | 0 | 1024 | 32 | 32 |
| 14 | African pygmy | M | 8 | 37.8 | IM | 0 | — | 0 | 256 | 64 | 64 |
| 15 | African pygmy | M | 11 | 62.8 | IM | 0 | — | 0 | 16 | 8 | 0 |
| 16 | African pygmy | F | 10 | 22.5 | IM | 0 | — | 0 | 1024 | 256 | 32 |
| 17 | African pygmy | F | 10 | 26 | IM | 0 | — | 0 | 256 | 32 | 16 |
| 18 | Kinder | M | 9 | 65 | SC | 0 | 16 | — | 128 | 128 | 32 |
| 19 | Kinder | M | 9 | 88.5 | SC | 0 | 8 | — | 32 | 64 | 0 |
| 20 | American pygmy | F | 9 | 32 | SC | 0 | 16 | — | 256 | 64 | 16 |
| 21 | American pygmy | M | 9 | 46 | SC | 0 | 8 | — | 64 | 32 | 16 |
| 22 | American pygmy | M | 9 | 45.5 | SC | 0 | 8 | — | 16 | 8 | 0 |
| 23 | American pygmy | M | 9 | 45 | SC | 0 | 8 | — | 64 | 32 | 8 |
| 24 | Nubian | M | 10 | 100.4 | SC | 0 | 0 | — | 64 | 8 | 0 |
| 25 | Nubian | M | 10 | 109.9 | SC | 0 | 8 | — | 64 | 16 | 0 |
| 26 | African pygmy | M | 15 | 47.8 | SC | 0 | 0 | — | 128 | 16 | 8 |
| 27 | African pygmy | M | 10 | 74.1 | SC | 0 | 0 | — | 64 | 8 | 0 |
| 28 | African pygmy | M | 10 | 30.3 | SC | 0 | 0 | — | 32 | 0 | 0 |
| 29 | African pygmy | F | 10 | 41.3 | SC | 0 | 0 | — | 64 | 8 | 0 |
| 30 | African pygmy | F | 10 | 35.5 | SC | 0 | 0 | — | 128 | 16 | 0 |
| 31 | African pygmy | F | 10 | 25.1 | SC | 0 | 0 | — | 32 | 0 | 0 |
Day 0 represents the sample taken immediately before initial vaccination; a booster dose was administered on day 21 (SC group) or 28 (IM group). Antibody titers at days 21, 28, 42, 90, and 190 after initial vaccination are reported.
Goat's mean antibody titers to SARS-CoV-2 at designated time points relative to vaccination.
| Days from first vaccination administration | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0 | 21 | 28 | 42 | 90 | 180 | |||||
| Route | IM | SC | SC | IM | IM | SC | IM | SC | IM | SC |
| Median | 0 | 0 | 8 | 0 | 1,024 | 128 | 64 | 32 | 32 | 4 |
| Range | 0–0 | 0–0 | 0–64 | 0–0 | 16–2,048 | 16–2,048 | 8–256 | 0–128 | 0–64 | 0–32 |
| n | 9 | 22 | 22 | 9 | 9 | 22 | 9 | 22 | 9 | 22 |
Number and proportion of goats with detectable positive titers (≥ 1:8) for SARS-CoV-2 at designated time points relative to initial vaccination.
| Day | Route | n goats with detectable titers | n tested | Proportion of goats with detectable titers (%) | P value |
|---|---|---|---|---|---|
| 0 | IM | 0 | 9 | 0 | |
| 0 | SC | 0 | 22 | 0 | |
| 21 | SC | 15 | 22 | 68 | P < .001* |
| 28 | IM | 0 | 9 | 0 | |
| 42 | IM | 9 | 9 | 100 | P = .499 |
| 42 | SC | 22 | 22 | 100 | |
| 90 | IM | 9 | 9 | 100 | P = .350 |
| 90 | SC | 20 | 22 | 91 | |
| 180 | IM | 8 | 9 | 89 | P = .044* |
| 180 | SC | 11 | 22 | 50 |
Chi-square or Fisher's exact test comparing the proportion of goats with positive detectable titers (≥1:8) at each time point between the groups (SC vs IM) is reported.
P value < .05 denotes significantly different.
Goat serum titers were statistically significantly different in the IM group between all days except for day 0 vs 28, day 42 vs 180, day 90 vs 180, and in the SC group between all days except day 21 vs 180 and day 90 vs 180 (Figure 1). In addition, there was no statistically significant difference between titers between SC and IM administration on days 0 (P = 1.00), day 21/28 (P = .078), day 42 (P = .268), or day 90 (P = .7783). However, on day 180 the IM group had a higher titer than the SC group (P < .0001) (Figure 1). On day 42, serum titers peaked for 94% of all goats (n = 29). By day 90, 87% of goats (n = 27) showed waning serum titers (still detectable, but lower than peak), and 94% (n = 29) of goats still had detectable serum titers. On day 180, 45% of goats (n = 14) had no detectable antibody at a 1:8 dilution.
Antibody titers to SARS-COV-2 detected by virus neutralization on days 0, 21/28, 42, 90, and 180 for 31 domestic goats that received 1 mL of vaccine against SARS-COV-2 (Mink Coronavirus Vaccine, Subunit; Zoetis) either SC (SC group; n = 22; green) or IM (IM group; 9; blue) on day 0. Vaccines were boostered on day 21 (SC group) or 28 (IM group). This study was conducted between SEP 27, 2021 and JUN 01, 2022. For each box plot, the horizontal line in the box represents the median; the upper and lower limits of the box represent the first and third quartiles, respectively; the whiskers represent the maximum and minimum titers for each time point; each circle represents the results for 1 goat, and any dots outside of the box and whiskers represent outliers.
Citation: American Journal of Veterinary Research 84, 10; 10.2460/ajvr.23.05.0117
Discussion
Our study demonstrated that SC and IM administration of an experimental SARS-CoV-2 vaccine are similarly effective in generating a humoral response in domestic goats with either a 21 or 28-day dosing interval. Before vaccination, there was no detectable antibody to SARS-CoV-2 in any goat at a 1:8 dilution. Animals in 1 facility (n = 9; 29%) may have been exposed to an enteric coronavirus during an outbreak of winter dysentery among closely housed nondomestic antelope species and Watusi cattle (Bos taurus indicus) 2 years before the present study. The coronavirus responsible for the outbreak of winter dysentery was sequenced as a waterbuck (Kobus ellipsiprymnus) associated strain. The lack of detectable antibodies before vaccination may be due to either a lack of cross-neutralization between the 2 coronaviruses (SARS-CoV-2 and bovine coronavirus) or waning antibodies during the approximately 2 years between the outbreak and study period.
There is currently no consensus regarding the correlation between antibody titer and resistance to SARS-CoV-2 infection in humans. While some humoral immunity data is available, there is little information regarding the role of cellular immunity. Some human SARS-CoV-2 studies consider a neutralizing titer of 16 to be protective against infection.18 The present study was not a challenging study and the antibody response to protect against infection has not been established in goats, but it is worth noting that a titer of ≥16 was achieved by all goats by day 42. Aside from the day 21 vs day 28 and day 180 time points, no statistically relevant differences were observed between the 2 investigated protocols (SC 21 days apart and IM 28 days apart). Due to an outbreak of COVID in human staff at 1 institution that interfered with the planned protocol, the 9 goats at that institution were administered a booster dose on day 28 rather than day 21. Notably, these 9 goats were in the IM group. The vaccine is recommended for a booster dose to be administered 21 days after initial administration. While 68% of the SC group had a detectable serum titer on day 21, none of the IM group had detectable neutralizing titers on day 28. It is unknown whether the IM group would have had detectable neutralizing titers if they had been sampled on day 21, or whether the IM route of administration may have resulted in a delayed rise in detectable serum-neutralizing antibodies. However, all goats from both the SC and IM groups had detectable titers on day 42, suggesting that both routes of administration and duration between doses are effective.
Peak neutralizing titers for all goats occurred on day 42. On day 180, 61% of goats still had detectable neutralizing titers (Figure 1). The proportion of goats with detectable titers at day 180 was statistically higher in the IM group vs the SC group (89% vs 50%) but the cause and clinical relevance of this difference are unknown and the small sample size in this study increases the risk of random error (Table 2). These serum-neutralizing titers only measure the humoral response to vaccination via the measurement of circulating antibodies and do not provide information on cellular-mediated immunity and memory cell response. It is possible that the goats may mount a robust amnestic response if they were to receive a third booster vaccination, or if they were exposed to SARS-CoV-2, but these possibilities were not evaluated in the present study. As these goats are collection animals, none of them were challenged with virulent SARS-CoV-2. None of the goats were diagnosed with COVID-19 during the duration of this study, including goats from the facility that had an active human COVID-19 outbreak among the staff.
The experimental SARS-CoV-2 vaccine was developed for use in mink. As such, the amount of antigen and adjuvant in the formulated 1 mL dose volume was optimized for mink, which are much smaller in physical size than goats. Due to the larger weight of the goats, it is possible that differing antigen and/or adjuvant concentrations or increased dosage may have increased the peak titers and duration of detectable neutralizing antibodies.
Limitations to this study include small sample size and age bias (as all study animals were considered middle-aged to geriatric); in humans, elderly individuals may have impaired B cell production and a compromised adaptive immune system.19,20 Intuitively, this may be true of geriatric goats as well. In our study, direct exposure to COVID-19 from humans or other animals was also not fully evaluated. The goats in this study were petting zoo animals that were hand-fed and had close interactions with zoo patrons and staff. Thus, the goats in this study may have been naturally exposed to COVID-19 during the study period through caretaker (especially at the zoo with an active human outbreak) and/or these guest interactions, further complicating the interpretation of their serum titers.
These data provide important information about the antibody responses in vaccinated animals and will contribute to the veterinary community's understanding of vaccine response in caprids, which may be extrapolated to other ruminants in both livestock and zoological setting.
Acknowledgments
The authors thank the zookeepers and veterinary technicians at Binder Park Zoo, Potter Park Zoo, Saginaw Children's Zoo, and John Ball Zoo for their assistance and care of the animals. We also thank the Virology Laboratory at the Animal Health Diagnostic Center at Cornell University College of Veterinary Medicine for the samples by VN assay.
Disclosures
Dr. Hardham is an employee of Zoetis, Inc.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to declare.
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