Winning by a nose in the fight against COVID-19

We are still in the early days of the age of omicron, and there is much that we do not know about this variant of COVID-19. But we do know that it is more transmissible than other variants and that it arose in a part of the world where only a small percentage of the population was vaccinated. 

In the film “Contagion,” for which Larry Brilliant and W. Ian Lipkin were scientific advisers, Centers for Disease Control and Prevention (CDC) scientist Ally Hextall, played by actor Jennifer Ehle, injects herself with an experimental vaccine against the pandemic virus MEV-1. In a later scene, CDC Director Ellis Cheever, played by Laurence Fishburne, gives a child the intranasal vaccine that ultimately ends the pandemic.

We recommended the filmmakers use an intranasal vaccine because it would be easy to manufacture worldwide, distribute and deliver. In addition to reducing barriers to access, it would also be more effective at preventing infection by providing what is called mucosal immunity, an immune blockade in the nose, where the virus first enters the body. 

However, despite the many advantages of intranasal vaccines, only eight of 137 vaccines listed in clinical trials by the World Health Organization (WHO) are intranasal. All the COVID-19 vaccines approved for use by the WHO, including those that have received emergency use authorization by the United States Food and Drug Administration, require intramuscular injection. Clinical trials confirm that these vaccines reduce the risk of severe disease in those who take them. What they have not done, however, is dramatically reduce virus transmission and infection. For that, we would benefit from intranasal vaccines.

The vast majority of antibodies elicited by intramuscular vaccines are the types (IgM or IgG) that circulate in blood and tissues. A small minority are the type (IgA) that are distributed at the mucosal surfaces of the nose, eyes and mouth, where we are most vulnerable to respiratory viruses such as SARS-CoV-2. This limitation has become even more apparent with the emergence of the omicron variant that has led to large outbreaks of infection in both fully vaccinated and boosted individuals. 

In contrast, while intranasal vaccines also elicit antibodies and T cells that circulate throughout the body, they are most efficient at inducing the production of the antibodies that can bind to viruses before they invade mucosal surfaces such as the lining of the nose, which has the highest concentration of ACE2, the receptor for the spike protein of SARS-CoV-2.

There are encouraging results in monkeys and rodents that have received intranasal vaccines containing the portion of the SARS-CoV-2 virus that binds to the ACE2 receptor. Vaccinated animals develop IgA as well as IgM and IgG antibodies to SARS-CoV-2. When inoculated with infectious SARS-CoV-2, they not only are protected from disease but also have low or undetectable levels of virus in their nasal passages.

The holy grail of herd immunity — the percentage of the population that would need to be immune to the virus through infection or vaccination — is a receding target. The already challenging estimate was thought early in the pandemic to be near 70 percent coverage. After the first variants, the estimate increased to near 80 percent. And with the more transmissible omicron variant, it is now estimated that, if it could be reached at all, it would require more than 9 out of every 10 to be vaccinated.

The most important factor in the emergence of variants is unvaccinated people within whom SARS-CoV-2 reproduces and evolves to even greater fitness for growth in humans. Global vaccination is the only way for us to starve the virus of the opportunity for creating additional new variants.      

The major impediments to global vaccination are hesitancy, production and delivery. A study in the United Kingdom of more than 15,000 adults reported an injection phobia in approximately 10 percent of vaccine hesitant individuals and found that injection fears were highest in younger, Black and Asian individuals. 

A shift to less invasive intranasal vaccines should result in improved compliance. Intranasal vaccines will still require regulated, rigorous manufacturing processes; nonetheless, they will not need highly trained vaccinators or the level of sterility required with injectable vaccines. Furthermore, none of the intranasal vaccines in development are as perishable as the RNA vaccines. In short, intranasal vaccines should be less expensive to manufacture, transport and administer.

What are the downsides? We have limited experience with intranasal vaccines, and our vaccine manufacturing facilities are designed to produce injectable vaccines. The only intranasal vaccines in common use are against influenza viruses, which have adapted to grow in the colder environment of the nose (34 degrees centigrade) rather than the lungs (37 degrees centigrade), where they can cause severe disease. There is a hypothetical increase in risk for facial muscle weakness, better known as Bell’s palsy. Although not life-threatening, it could be disfiguring. However, the only intranasal vaccine found to cause this problem was an inactivated influenza vaccine that included an immune system stimulant. That vaccine was discontinued in Europe and was never used in the United States. Furthermore, risk would be mitigated by following the same rigorous safety and efficacy testing applied to the injectable Pfizer-BioNTech, Moderna and Johnson & Johnson vaccines.      

We do not propose that the world abandon the injectable vaccines that have already saved millions of lives. Indeed, the ideal vaccine cocktail may include injectable and intranasal components. Nonetheless, as the pandemic enters year three without signs of abatement, it’s time to think about new strategies for containing the contagion.

W. Ian Lipkin is John Snow Professor of Epidemiology and director of the Center for Infection and Immunity in the Columbia University Mailman School of Public Health, founding director of the Global Alliance for Preventing Pandemics and a member of the WHO Global Outbreak Alert Response Network. 

Larry Brilliant is chief executive officer of Pandefense Advisory, a former member of the WHO Smallpox Eradication Program, epidemiology professor at University of Michigan, executive director of Google.org and CEO, The Skoll Global Threats Fund and co-founder of the Seva Foundation.

Lisa Danzig is an infectious disease physician and vaccine expert at Pandefense Advisory, chief medical officer at Excision BioTherapeutics and a former epidemiological intelligence officer at the Centers for Disease Control and Prevention.