The Critical Role of Vaccine Delivery Methods: The Case for Intranasal for Certain Microbes and Situations

We are all hearing these days about the different types of vaccines regarding COVID-19. For instance, the Pfizer-BioNTech and Moderna vaccines are both mRNA, whereas the Johnson & Johnson/Janssen is a recombinant adenoviral vector vaccine. All three are administered intramuscularly (a form of parenteral administration).

While these vaccines provide protection against serious infection in vaccinated people, some of the vaccinated are experiencing breakthrough cases and can still transmit the Delta, Delta Plus, Lambda and potential other arising mutants such as the Mu variant of SARS-CoV-2 (the virus that causes COVID-19). 

The problem is that the currently available vaccines do not necessarily produce local antibodies in the nose and nasal passages. They produce systemic antibodies. Even though they are systemwide in the blood, they apparently are not effectively reaching all tissues.

Why? Because of the delivery method, which is intramuscular. Remember, the primary port of entry for SARS-CoV-2 is the nose. Researchers are experimenting with intranasal vaccines against SARS-CoV-2 and are finding that animals vaccinated intranasally had substantially less infectious virus in their nasal passages than unvaccinated animals. They are also discovering that intranasal vaccines produce antibodies in the blood, just like intramuscular. Plus, intranasal prevented infection in both the upper and lower respiratory tract.

Many researchers are saying that because of the nature of SARS-CoV-2, intranasal vaccines should have been and should be now explored as much as intramuscular. 

There are advantages to intranasal vaccines. Intranasal vaccines may save costs for mass vaccinations, because much less antigen is needed and it is a safe and easy administration route. They don’t require syringes that can add to medical waste and expense. Plus, a health care provider probably would not have to give it. 

Of course, when vaccines are produced we have to consider several factors, such as:
A). the microbe itself (is it a virus, bacterium, fungus, parasite?);
B). how the microbe is primarily transmitted (airborne or feces?);
C). how transmissible, zoonotic and deadly the microbe is;
D). how the vaccine was produced and the additional components in it;
E). the type of vaccine (live attenuated/modified live, inactivated/killed, mRNA, recombinant);
F). how the vaccine is delivered or administered (injection/parenteral, orally, aerosol through nose, skin patch, or gene gun);
G). how effective the delivery route combined with the type of vaccine is;
H). how long the vaccine lasts;
I). if the vaccine will provide protection against variants;
J). if the vaccine is safe and efficacious; and,
K). if the vaccine produces the intended results where we need it to. 

It is interesting that major pharmaceutical companies relied on the traditional model of parenteral vaccines against SARS-CoV-2, even though intranasal vaccines have been around for ages for companion pets. (To be fair, most of the intranasal vaccines for companion pets were developed as injectables at first.) Plus, there is an intranasal vaccine against influenza on the market for humans. 

Let’s look at a couple of the popular intranasal vaccines available.

Bordetella for Dogs

First, let’s be clear. Dr. Dodds and Hemopet do not recommend the vaccine against, Bordetella bronchiseptica, a bacterium that is a member of the canine kennel cough complex. It is considered a non-core vaccine by the World Small Animal Veterinary Association (WSAVA) and the American Animal Hospital Association (AAHA) too. 

However, we realize that extenuating circumstances occur that may make it unavoidable. A good example is you are going on a business trip, need to board your companion dog, and the boarding facility requires proof of vaccination against Bordetella bronchiseptica, and will not accept a waiver. 

In this instance, we prefer either the live attenuated oral or intranasal Bordetella vaccines instead of the killed injectable. Note that the intranasal vaccine can spray around the face and eyes and anyone nearby. 

A 2013 study from the University of Wisconsin – Madison demonstrated that local secretory (in the nasal passages) antibody IgA immunity was induced by both the oral and intranasally administered vaccines – something that is unachievable with the killed injectable version. So, your dog would have local and systemic protection against the bacterium.

Additionally, the oral and intranasal versions of Bordetella cause the body to release interferon (proteins that are part of the body’s natural defenses) which helps cross-protect against the other upper respiratory viruses. Injectable Bordetella vaccine does not offer this added benefit. 

Core Vaccines for Cats

The American Association of Feline Practitioners (AAFP), AAHA and WSAVA all agree that the core vaccines for cats are against feline calicivirus (FCV), feline herpesvirus-1 (FHV-1), feline panleukopenia (FPV), and feline leukemia (FeLV). With the exception of the routine use of FeLV vaccine, Dr. Dodds also recommends vaccinating cats against FPV, FHV-1, and FCV.

Why do we recommend these vaccines? Because of the hardiness, persistence and easy transmissibility of the viruses. 

Panleukopenia (FPV) – Infected cats can shed and pass panleukopenia to susceptible cats through urine, feces, nasal secretions, and even from fleas that jump off infected cats. While an infected cat may only shed the virus for a day to or two, the virus can survive up to one year in the environment. 

Calicivirus (FCV) – Calicivirus is spread via through direct contact with the saliva, nasal mucus, eye discharge, and through sneezes (aerosols). Cats can shed this virus up to three weeks after infection. However, some cats become long-term carriers and can continue to shed it for months. Additionally, FCV can survive on surfaces for up to a month in certain environments.

Herpesvirus-1 (FHV-1) – Unlike FCV and FPV, herpesvirus-1 only survives on surfaces that are moist. Once the surface is dry or the secretions have dried, the virus dies. Similar to the other viruses, FHV-1 is spread in saliva, eye discharge and nasal passages. 

FCV, FHV-1 and FPV are all available as attenuated live parenteral, inactivated parenteral, and attenuated live intranasal.

While certain and rare instances do require that veterinarian need to give vaccines by injection, Dr. Dodds recommends the intranasal for all three of these viruses in the majority of cases. The intranasal vaccines provide faster and more complete protection.

Besides these benefits, sarcomas can occur at the vaccine injection site, albeit rarely.

The most disturbing concern here is that research has shown that parental vaccines against FCV, FHV-1 and FPV may cause chronic kidney disease (CKD) in cats. 

Why could the parental vaccines cause CKD?

A kidney cell called Crandell Rees Feline Kidney Cell (CRFK) is often used to help grow these feline vaccine viruses. Using something like CRFK to grow vaccine cell lines is normal. For instance, killed pet influenza vaccines are often produced in hen eggs. 

Unfortunately, proteins derived from CRFK may persist in the parental vaccines and cause the development of CKD. In fact, a 2010 study by Whittemore et al. demonstrated that cats given either the inactivated or live attenuated versions of the parental vaccines had developed anti-CRFK antibodies, which could lead to CKD. On the other hand, no significant differences of anti-CRFK antibodies were detected in cats given the live attenuated intranasal vaccine. 

The research team noted, “The difference in magnitude of responses within groups is most likely related to route of administration, with subcutaneous administration of CRFK lysates resulting in greater systemic uptake by antigen-presenting cells and greater production of IgG than intranasal administration, whereas intranasal administration would be anticipated to stimulate local production of IgA. It is possible but less likely that the differences reflect differences in CRFK concentrations among vaccines.”

References

2017 AAHA Canine Vaccination Guidelines. American Animal Hospital Association, 3 Feb. 2018, https://www.aaha.org/aaha-guidelines/vaccination-canine-configuration/vaccination-canine/

Birkhoff, M. et al. “Advantages of Intranasal Vaccination and Considerations on Device Selection.” Indian Journal of Pharmaceutical Sciences vol. 71, no. 6 (2009): 729–731, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846493/

Core Vaccines for Pet Cats. American Animal Hospital Association, 2020, https://www.aaha.org/aaha-guidelines/2020-aahaaafp-feline-vaccination-guidelines/core-vaccines-for-pet-cats/

“Intranasal COVID-19 Vaccine Effective in Animal Studies.” National Institutes of Health, U.S. Department of Health and Human Services, 10 Aug. 2021, https://www.nih.gov/news-events/nih-research-matters/intranasal-covid-19-vaccine-effective-animal-studies

Larson, Laurie, et al. “A Comparative Study of Protective Immunity Provided by Oral, Intranasal and Parenteral Canine Bordetella Bronchiseptica Vaccines.” The International Journal of Applied Research, vol. 11, no. 3, 2013, pp. 153–160, https://doi.org/http://www.jarvm.com/articles/Vol11Iss3/Vol11Iss3Schultz.pdf

Lawson, J S et al. “Characterisation of Crandell-Rees Feline Kidney (CRFK) cells as mesenchymal in phenotype.” Research in veterinary science vol. 127 (2019): 99-102, doi:10.1016/j.rvsc.2019.10.012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863388/

Vaccination Guidelines. World Small Animal Veterinary Association, 9 Aug. 2021, https://wsava.org/global-guidelines/vaccination-guidelines/

Whittemore, J.C., et al. “Antibodies against Crandell Rees Feline Kidney (CRFK) Cell Line Antigens, α-Enolase, and Annexin A2 in Vaccinated and CRFK Hyperinoculated Cats.” Journal of Veterinary Internal Medicine, vol. 24, no. 2, 1 Mar. 2010, pp. 306–313, https://doi.org/10.1111/j.1939-1676.2010.0476.x, https://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2010.0476.x.

Scroll to Top