There has been a great deal of buzz around nasal vaccines over the past two years. The idea is simple enough: stop infection at the source. Since SARS-CoV-2 enters through the nasal passages and lungs, bolstering our immune system in those areas may help keep the virus out, preventing infection in the first place. Our current vaccines only protect against disease, so a booster that helps stave off acquisition of infection would be a welcome addition to our pandemic-control toolbox. The issue? I’m not optimistic nasal vaccines will offer broad, long-term protection. What follows is a brief overview of novel data on mucosal immunity and a reminder that, despite the excitement, we would do well to temper our expectations. 

Sentries on the Wall: Immunoglobulin A 

Most of the antibodies produced following intramuscular vaccination are of the Gamma variety (IgG); these primarily circulate the blood and bodily tissues. Yet, they have trouble getting into mucous membranes. Think of mucous membranes as a kind of interior skin, providing the outermost barrier of protection against foreign threats in the digestive, reproductive, and respiratory systems. Essentially, the mucosa functions like a fortified wall that pathogens need to penetrate if they wish to gain access into the body proper. Since IgG antibodies struggle to access the mucosa, they can’t stand sentry on the fortified wall. Instead, they have to wait for the pathogens to enter before they can begin their offensive. 

Unlike IgG antibodies, immunoglobulin Alpha (IgA) antibodies are right at home in mucous membranes. Here, they provide the first line of defense; if present in high numbers, IgA antibodies can stop pathogens before they ever even manage to enter the body. As a result, some researchers have marked them as prime candidates for achieving “sterilizing” immunity — immunity that prevents infection. 

Grounds for Hope  

Working out of the Karolinska Institutet and Danderyd Hospital in Sweden, Marking et al. made use of regular blood samples and polymerase chain reaction (PCR) tests to trace immune responses in 2,150 healthcare workers from the spring of 2020 onwards. 

In a previous screening study involving the same cohort—conducted between January and February 2022— the researchers discovered that “those who had high levels of wild-type spike-specific mucosal IgA at enrollment had a significantly lower risk of subsequent omicron breakthrough infection than did those with lower levels.” Importantly, this protective effect did not extend to participants with high levels of IgG antibodies at enrollment. They also found that, although IgG levels increase with both infection and vaccination, only natural infection significantly boosted IgA levels.

Now, the researchers report that the protective effect conferred by nasal mucosal IgA antibodies is maintained for roughly seven months (Figure 1); despite waning titers, IgA levels remained above the protective threshold in 94% of previously-infected participants and 58% SARS-CoV-2-naive participants. 

An earlier study, conducted by researchers at Imperial College London and now published in eBioMedicine, found similar results. Between February 2020 and March 2021, Liew et al. collected nasal and blood samples from 446 patients hospitalized with Covid-19. Sampled antibodies were tested against the spike and nucleocapsid proteins of the wild-type SARS-CoV-2, the Delta variant, and the BA. 1 lineage of the Omicron variant. 

The group of scientists found that nasal IgA levels persisted for roughly nine months. After this, they dropped back down to pre-Covid-19 levels, as confirmed by nasal samples collected prior to the onset of the pandemic. This period was even shorter for IgA that binds Omicron. 

Again, intramuscular vaccination boosted IgG levels but had little effect on IgA levels — any increase that was observed was minimal and short-lived. 

Liew et al. conclude that, if we want vaccines that are able to prevent infection and transmission, we will need them to significantly boost nasal IgA levels, which our current vaccines fail to do. Nasal vaccines, they suggest, hold the most potential for achieving this. 

Grounds for Doubt

Although the above findings are promising, there are still a few reasons for doubt. Perhaps the most troublesome is the fact that even natural infection with SARS-CoV-2 does not permanently prevent reinfection down the line; viral variation and waning immunity mean the virus has been able to attack us again and again, wave after wave (Figure 1). 

FIGURE 1.  7-day moving average of SARS-CoV-2 cases, COVID-19 hospital admissions, and in-hospital deaths in South Africa, March 5, 2020, to Jan 22, 2022. SOURCE: “Clinical severity of COVID-19 in patients admitted to hospital during the omicron wave in South Africa: a retrospective observational study” JASSAT ET AL. 2022

If natural infection, which enters through the respiratory tract, doesn’t provide long-lasting protection from reinfection, why should nasal vaccines? In general, if natural infection doesn’t provide sterilizing immunity, it is unlikely that vaccines will. One has only to look to influenza and cold-causing coronaviruses as examples of this unfortunate fact — a thorn in the side of vaccinologists. 

Another issue —albeit closely related to the first— is the fact that antibodies wane quickly, and IgA antibodies more quickly and drastically than others. So even if we use nasal vaccines as boosters, we would need to top up every four or five months. This may work in the short term, but in the long term people will grow tired, as they have with current booster shots, and uptake will drop off. The break-neck pace of viral mutation also has to be taken into account. For vaccines and antibodies to be most effective, they need to match the dominant circulating variant; with new variants constantly vying for top spot, the window of efficacy shrinks. In practice, this leaves us always one step behind.

If we want a vaccine that offers long-lasting, broadly neutralizing protection, nasal vaccines likely won’t be the best approach. In the meantime, our efforts may yield better returns directed at developing highly-active combinatorial drugs that offer pre- and post-exposure prophylaxis. This has worked incredibly well in the battle against HIV/AIDS —for which there is still no vaccine— and can work equally well in the case of Covid-19. Continued research in the field of vaccines cannot come at the cost of tunnel vision; we must maximize all of the resources at our disposal.