Matthew Pennington, PhD

Viral Vector Vaccines for Animal Diseases are Common

So why don’t we have more of these vaccines for use in humans?

The COVID-19 pandemic has spurred the widespread introduction of new vaccine technologies into humans. In April 2020, we wrote about some of the early vaccine candidates. One year later, there are two adenoviral vector vaccines and two mRNA vaccines being delivered into arms worldwide. mRNA vaccines are truly new, only studied up to this point in research and clinical trials. However, viral vector vaccines have been extensively used in veterinary medicine and even previously been approved for humans. By understanding these other viral vectors, we can understand how the COVID-19 vector vaccines were developed, how they work, and the challenges that still face this technology.

The first step in creating a viral vector vaccine is to select and modify a virus, turning it from an infectious agent into a vaccine delivery platform. We previously explained in more detail how this is accomplished. A key region of the viral genome is typically removed, rendering the virus unable to grow. Alternatively, a virus that does not cause disease may be used as the vector. Next, an antigen, a piece of the target pathogen against which we want to vaccinate, is added into the vector genome. There are two primary approaches to using a viral vector vaccine to display this antigen to the immune system— pseudotyping and genetic transfer. Table 1 provides an overview of many of the common viral vectors currently used in animals and humans.

Table 1: Overview of select approved viral vector based vaccines for use in humans and animals. For more information refer to: Draper and Heeney 2010, Vrba, et al 2020, and the USDA.

Chart of Viral Vector Vaccines in AnimalsPseudotyping Viral Vectors

Pseudotyping uses the unique proteins present on the surface of each virus as the antigen, as typically these are potent immune response stimulators. The vector is modified to remove its own surface proteins and instead display the surface proteins from the virus against which we are vaccinating. They are called pseudotyped vectors as they mixes and matches different virus components together. Antibody and cell-mediated immune responses are then generated targeting this new surface protein.

Pseudotyped vectors have proven to be especially useful in vaccinating wildlife against rabies. One product consists of a weakened vaccinia virus that displays the rabiesvirus glycoprotein on its surface. The vaccine is packaged inside of a food bait and can be distributed in an environment. Coyotes, racoons, skunks, and other animals eat the bait, releasing the vaccine into their bodies, and develop protection from rabies. This vaccine has been tested in more than 50 species, including target and non-target species, with no serious adverse reactions noted in any species. More than 250 million doses of the vaccine have been used globally, helping to reduce the distribution of rabies.

Pseudotyped vaccines have already been approved for humans. In December 2019, the US FDAViral Vector Vaccines in Animals approved an Ebola vaccine consisting of a modified vesicular stomatitis virus expressing the ebolavirus glycoprotein on its surface. This vaccine induced robust and rapid antibody responses and proved to be 97.5% effective in clinical trials, a truly impressive response. However, it is only recommended for those responding to Ebola outbreaks, working directly with the virus, or for ring vaccination to reduce spread from an infected person. Additionally, we still do not have a good understanding of the types of immune responses that protect against Ebola, and therefore, it is hard to predict how long the protection will last.

Genetic Transfer Vectors

Instead of changing the surface of the vector, the genetic transfer strategy modifies the DNA or RNA genome of the vector to drive the cells themselves to produce the antigen against which we wish to vaccinate. This is the strategy that both adenoviral COVID-19 vaccines use. When injected, cells of the body pick up the virus, break it down, and release the DNA inside of the cell. The cell’s normal machinery recognizes the DNA and uses it as instructions to produce the viral antigen itself. This antigen then can go on to stimulate both antibody and cell-mediated immune responses.

This strategy has been widely used to develop vaccines for cats and dogs (Table 1). Many of these vectors were developed by the same company using a live canarypox vector. Pox viruses have large DNA genomes, enabling them to carry in a large volume of foreign DNA and are known for their ability to stimulate strong immune responses. Canarypox is a particularly useful vector as it can replicate in bird cells but has an abortive infection in mammalian cells. This means that it can enter mammalian cells, delivering the gene for the antigen, but not replicate or cause disease. This makes canarypox a very safe delivery vector. Canarypox is being explored as a vector for human vaccines. For example a clinical trial for a human immunodeficiency virus (HIV) vaccine based on canarypox found that it reduced HIV infections by 31.2% compared to the non-vaccinated group, when given sequentially with a vaccine containing a protein form HIV’s surface. While promising and demonstrating that this strategy can be effective— and the first and thus far only evidence of a vaccine-induced protection against HIV— the vaccine combo was deemed to have to low an efficacy to seek approval for widespread use.

Flock of chickens -- poultry viral vector vaccine storyGenetic transfer vaccines have also found success in the poultry industry, where infectious disease control with traditional vaccines continues to be a challenge. Vaccines consisting of live turkey herpesvirus modified to additionally transfer in genes for other viruses’ antigens have been widely used. Marek’s disease is one of the most highly contagious diseases in poultry. Turkey herpesvirus is used as the vector because it causes no apparent disease in chickens, but is still able to induce immunity that cross-protects against the other herpesviruses that causes Marek’s disease. By also transferring in genes against other avian pathogens, such as avian influenza, infectious bursal disease virus, Newcastle disease virus, and fowl laryngotracheitis virus, at the same time, protection against multiple targets can be achieved with a single vaccine.

Why are viral vector vaccines so highly prized?

Viral vector vaccines solve many of the problems that plague traditional vaccine development. Vectors are thought to be much safer. The vector itself is modified to not replicate or a vector that does not cause disease is selected. As only individual genes from another virus are given, there is no possibility for the vaccine to cause disease.

It can be relatively quick and easy to develop new vector vaccines against multiple targets. The same vector platforms can be used, and only the antigens need to be swapped. This is exemplified by the canarypox vaccine vector used for many different cat and dog viruses, the turkey herpesvirus vector used for many poultry diseases, and the the adenovirus that was extremely useful in combating the COVID-19. Indeed, similar vaccines in development against SARS and MERS were quickly altered and repurposed into COVID-19 vaccines.

Traditional vaccine types may only induce antibody-based or cell-based immunity, but not both. In contrast, viral vaccines can be strong inducers of both arms of adaptive immunity, potentially providing a greater level of protection. Depending on the vector used, they may also be much more stable, making them ideal for delivery to remote locations.

Adenovirus particle for viral vector vaccine in animals articleThere are some drawbacks, however. People may have already encountered the virus being used as a vector. For example, adenoviruses can cause colds and upper-respiratory infections, among other symptoms, leading to the generation of anti-adenovirus responses. These responses could target and inactivate an adenovirus vector vaccine before it has a chance to deliver its genes. This is typically addressed by using viruses that are not commonly seen in the target population. For example, one of the COVID-19 vaccines is based on an adenovirus that naturally infects chimpanzees, which most humans do not ever encounter before vaccination. The other COVID-19 vaccine uses human adenovirus 26, which is uncommon in most populations. It can also be more difficult, labor intensive, and expensive to produce large quantities of viral vectors compared to traditional vaccine approaches.

If we have so many viral vectors for animals, why don’t we have more for humans?

Viral vector vaccines have been studied in both animals and humans for nearly 50 years. Veterinary medicine has proven to be at the forefront of and the first to adopt this technology. Companion animals and livestock have proven time and time again to be useful and more appropriate natural host models of infection for human diseases compared to traditional laboratory animals. The efforts made by veterinary medicine are arguably what has laid the groundwork to bring these vaccines to humans, including the new COVID-19 vaccines. Continued investment in the development and production of animal vaccines will be critical to advancing the technology, for the benefit of both human and animal health.

The challenge in the translational application of viral vector vaccines from animals to humans largely is due to safety concerns. There is a very tightly regulated, time-consuming, and expensive process that any new medicine must go through to achieve regulatory approval to ensure their safety and efficacy. This process is more stringent for human products compared to animal ones, and it historically has taken 10-15 years for new vaccines to be approved. The past efforts to develop viral vector vaccines for other animal and human pathogens, combined with the overwhelming need for COVID-19 vaccines, allowed for the quick development of COVID-19 vaccines and an acceleration of the clinical and testing and regulatory review so that emergency use authorization could quickly be granted. These new vaccines were not rushed, but rather build on foundations laid by veterinary vaccines. It may be that one good thing that comes from the pandemic is the accelerated introduction of new vector vaccines for other human diseases.