*3.2.2 SARS-CoV-2 variants in domestic and wild animals*

The virus has been detected in domestic cats and dogs [14]. Therefore, the transmission from humans to domestic animals is plausible. Specifically, the B.1.1.7 (Alpha) variant has been identified in domestic cats as well as in domestic dogs [19]. In contrast it appears that cattle, goats, and sheep are not infected by the virus [20].

Among animals kept in zoos the virus has been detected in gorillas, tigers, pumas, cougars, Asian small-clawed otters, and snow leopards. The genetic variability of SARS-CoV-2 is evident from the 9 genomes identified in tigers, lions, and their keepers [21]. The B.1.1.7 (Alpha) variant has been detected in gorillas, lions, leopards, and tigers [20, 22]. In another study the B.1.617.2 (Delta) variant was reported in Asiatic lions from India [23]. Farmed wild animals have been diagnosed with SARS-CoV-2. Specifically, SARS-CoV-2 has been identified in American minks (*Neovison vison*) and in ferrets (*Musteal furo*) [20].

Therefore, this possibility of emergence of new variants is ever present due to SARS-CoV-2 spread to different ecological environments and newer animal reservoirs resulting in a subsequent risk for spillover into humans and other species.

### **3.3 Immunological determinants**

### *3.3.1 Herd immunity*

Lately, the phrase "Herd Immunity" is constantly brought up in news outlets, in commentaries, opinion pieces, and peer-reviewed articles. First introduced almost 100 years ago, it only recently gained popularity [24]. Although Herd Immunity is now a widely accepted concept, it may take on multiple meanings, each slightly different than the next. Some researchers consider Herd Immunity a threshold of the proportion of immune individuals that leads to a decline in infections or outbreaks [25, 26]. While others may use it to describe the proportion immune to a specific infection among a population or refer to it as a protective immunity pattern [25]. Herd Immunity is most referred to as the reduction of risk, of an infection, to susceptible individuals by the proximity and presence of immune individuals [25]. Herd Immunity may be used interchangeably as "indirect protection" or "herd effect". Regardless of the definition variations, Herd Immunity leads to one outcome – the reduction of infection incidence. This concept, in conjunction with vaccines, has contributed to some of the most important public health achievements in the 20th and 21st century such as the smallpox eradication, polio elimination, and other vaccine-preventable diseases. This section explores the concepts behind Herd Immunity and current and future implications during the COVID-19 pandemic.

### *3.3.1.1 Theories which constructed herd immunity*

Topley and Wilson (1923) were the first to coin the term "Herd Immunity" and specifically look at host resistance in comparison with mass infection. After first mention of Herd Immunity, the term and overall concept started appearing and developing soon after [27–29]. Dudley [27] explored the idea of a "herd" or community and how it could be defined. He defined the idea of "infection pressure" (i.e., fundamental parasite factor) which may be determined by the infectious agent distribution frequency rates which is in the members of the herd [27]. He claimed, infectious pressure reacts with Herd Immunity, the increase of one increases the other and then decreases it to zero. This introduced the idea of needing a minimum amount of Herd Immunity, a threshold, in order to keep the infectious pressure at zero. Furthermore, he mentioned those two factors contributed to the type, quantity, infection speed (i.e., now known as R0) and the frequency and distribution of cases and their severity [27].

Yet Herd Immunity had one large limitation—to provide protection, a high proportion of the population must be immune to the pathogen. Before immunizations individuals had to survive and pass the pathogen to become immune; depending on the pathogen, likelihood of survival and being left with life-altering morbidities varied. However, as concepts behind Herd Immunity were evolving, vaccinations were becoming a staple of public health practice, allowing a large proportion of the population to be safely immunized against specific pathogens. Vaccination allowed for the fulfillment of Herd Immunity at a much faster rate and safer manner. This allowed for the concepts to be turned into mathematical possibilities.

Before vaccination and Herd Immunity there were two main hypotheses as to why outbreaks would end even though not all susceptible were affected: (1) the agent naturally loses virulence (2) the dynamics between susceptible, infected,

and immune [26]. The later hypothesis, prevailed with its mathematical idea of "mass action principle" (MAP) [26]. This principle was based on a simple logical argument in favor of indirect protection given by Herd Immunity and became an epidemiological theoretical cornerstone. Eventually three theories converged into one general theory driving Herd Immunity: MAP, case reproduction rates (later called base reproductive rates [BRR]), and the Reed-Frost heterogenous population simulation approach [26]. The current formula used for Herd Immunity is H = 1–1/ R0 = (R0–1)/R0, where R0 is the BRR. H is the Herd Immunity threshold, the proportion of immunes needed in order to reduce incidence and R0 is derived from the duration of contagiousness of an infected individual, the likelihood of infection per contact between a susceptible person and an infectious person or vector, and the contact rate [30]. The BRR serves as an indicator of the contagiousness of an infectious agent—the higher the R0, the more transmissible. An R0 > 1 indicates an outbreak will continue, while a R0 < 1 indicates the end of an outbreak, if R0 = 1 then the outbreak is stable [30]. In novel outbreaks, where everyone is susceptible the R0 defines the infectiousness of a pathogen. However, as individuals pass the infection or become immunized, the number of susceptible decreases and immune increases, and although this does not technically reduce the BRR, because the definition of R0 assumes a completely susceptible population, one can use the effective reproduction number (R) in lieu, which is similar to R0 but does not assume complete population susceptibility and, thus, can be estimated with populations with immune members [30]. Efforts aimed at reducing the number of susceptible persons through vaccination would result in a reduction of the R value, rather than R0 value.
