The recent surge of COVID-19 in the southern U.S. in summer and early fall was fueled by the rise of the Delta variant storming through the unvaccinated population. But among the cases and hospitalizations were also some vaccinated people with breakthrough infections.
This week, the topic of breakthrough infections garnered even more attention with the passing of Colin Powell. The former Secretary of State was 84 years old and battling multiple myeloma when he died of COVID-19 complications, despite being fully vaccinated. This begs the question of whether there are other types of vaccines that can provide a stronger defense against breakthrough infections for those who are at greatest risk of serious breakthrough COVID-19.
Systemic vaccination may not act quickly enough to respond to the Delta variant. The role of local tissue immunity needs to be emphasized as this is where the ACE2 receptors are located. Once the virus infects the alveolar epithelial cells deep within the lungs, symptoms beyond runny nose will start and, very importantly, the now dominant Delta variant may evade aspects of the immune system.
This is especially true in people who have a weakened immune system — as was likely the case with Powell. The answer to greater protection from breakthrough COVID-19 may lie in a type of vaccine that hasn’t received enough attention to date: intranasal vaccines (INVs).
Intranasal Vaccines
Given the Delta variant with its associated high viral load, systemic vaccinations may not produce enough local tissue immunity in the portals of entry (oral cavity, nasopharynx, lower respiratory tract where ACE2 receptors are predominant in cilia and alveolar type 2 cells). INVs would fill in this gap by generating local tissue immunity.
INVs have proven to be effective against both human and animal respiratory diseases primarily by promoting local respiratory protection. However, there are limited data on the efficacy of INVs against respiratory coronaviruses. In veterinary medicine, the INV against the bovine respiratory coronavirus has shown some efficacy. Since we know veterinary medicine has successfully used nasal vaccines for other viruses for years, why not follow their lead?
The Risk of Breakthrough Infections
INVs may be especially important as we see more and more breakthrough COVID-19. Israeli data during the Delta wave showed declining protection from the Pfizer mRNA vaccine. Was the Delta variant evading the vaccine or was the person’s own immune system not fully robust? Or is there inadequate immune activation at local IgA at the portal of entry of the virus in the nasopharynx and lower respiratory tree with systemic vaccination?
Certain populations are at higher risk for breakthrough infections than others. Organ transplant patients don’t generate enough B- and T-cell function to produce high neutralizing antibodies. This is well-documented in kidney transplants where 50% of patients had a decent response but the other half remained at risk even after a booster shot. What about many others who may have a compromised immune system? In a U.K. study through June of this year, 4% of the total COVID-19 hospitalizations and deaths were among the country’s fully vaccinated population. Those at highest risk included people with Down syndrome, dementia, and Parkinson’s or other neurological diseases; bone marrow or solid organ transplant recipients; individuals receiving in-home care; and people with HIV/AIDS, cirrhosis, or who were receiving chemotherapy. For those at high risk, the list includes chronic obstructive pulmonary disease, coronary artery disease, and type 2 diabetes, among others.
Considering the recent case of Powell, what do we know about patients who have multiple myeloma? In one small study of 48 patients (and 104 controls) who received one dose of the Pfizer mRNA vaccine, we saw a low neutralizing antibody response. What would the response have been after a second dose, after a booster? A recent study also suggested poor T-cell responses for many of these patients. While Powell was fully vaccinated against COVID-19, his age and blood cancer put him at much higher risk for serious breakthrough illness.
Preventing Serious Breakthrough Infections
The COVID-19 vaccines currently available continue to offer substantial protection against severe disease and death for most people. Therefore, gaining a thorough understanding of which populations might be at greatest risk of serious breakthrough COVID-19 is key to understanding who may benefit from an INV, if one were to become available. For an at-risk person potentially susceptible to serious infection, the person could get a standardized validated blood test to measure COVID-19 neutralizing antibody, as done in the kidney transplant study referenced above. (A functional measure of T and B cells would provide even more information, but is not practical.)
Then, if the circulating IgG neutralizing antibody level is below a threshold value, that person may be a good candidate for an INV. This approach would supplement the bolstering of local tissue immunity. It’s possible that the immune deficit is due to low nasopharyngeal IgA despite high levels of circulating neutralizing antibodies. There is no practical measure available to assess the level of localized immune protection.
Should one of these individuals contract COVID-19 with symptoms, they would also be excellent candidates for receiving an oral antiviral, if authorized.
Broader Roles for INVs
In addition to the role as a supplement to systemic vaccination, INVs could serve a primary role for mass vaccination in areas of the world with large unvaccinated populations. Traditionally they are easier to distribute and to administer — often only requiring two sprays or two drops in each nostril — and there are no syringes, needles (and needle phobia), or freezers.
We should encourage the rapid completion of pivotal clinical trials of INVs, many of which are in progress. We need to have more options available, especially for those at greatest risk of breakthrough infections — and we need more clinical research on specific clinical groups of patients who may be at risk.
Daniel Teres, MD, is a critical care physician and clinical instructor in public health and community medicine at Tufts University School of Medicine in Boston. Diana M. Stone, PhD, MPH, DVM, is a professor at St. George’s University School of Veterinary Medicine. Martin A. Strosberg, PhD, MPH, is emeritus professor of political science, healthcare policy, and bioethics at Union College.