COVID-19 Vaccines May Not Prevent Nasal SARS-CoV-2 Infection and Asymptomatic Transmission

The pace of COVID-19 vaccine progress has been unprecedented, with >160 programs in preclinical and clinical trials. Clinical outcome measures within the lead candidates completing phase 3 studies are currently focused on safety and prevention of the COVID-19 syndrome. As early efficacy data become available, however, there has been increased focus on whether these systemic vaccines will also be “transmission blocking,” or capable of preventing localized SARS-CoV-2 infection and shedding within the upper airway.

Although viral vaccines generate cellular immunity with vaccine-specific memory CD4+ T helper 1 cells and CD8+ T cells, the principal mechanism by which injectable (eg, systemic) vaccines protect against respiratory infections is the development of humoral immunity through vaccine-specific serum IgG.¹ While preventing systemic replication, injectable vaccines provides only limited mucosal protection, largely through IgG transudation at the airway surface. To effectively prevent viral replication within mucosal primary target cells, adequate local production of secretory IgA (SIgA) is necessary, which generally requires a mucosal route of vaccination. For example, while the injectable inactivated polio vaccine and oral polio vaccine both produce systemic antibodies to prevent neurologic sequelae, the oral polio vaccine is far superior in generating a local SIgA response within the enteric mucosa where the poliovirus tends to enter.² Similarly, the intranasal influenza vaccine spray FluMist has been shown to provide comparable overall efficacy to the injectable vaccines while producing higher airway SIgA.³

The divergence in immune response between mucosal and systemic vaccination is derived from the fact that human mucosal surfaces contain a localized immune system composed largely of mucosa-associated lymphoid tissue, which contributes up to 80% of all immunocytes within the body. Given that it operates within a highly heterogenous and contaminated milieu, the mucosa-associated lymphoid tissue tends to be highly compartmentalized and, to some extent, functions independently of the systemic immune system. Consequently, following local antigen exposure, activated mucosal-derived B and T cells may only selectively populate the mucosa of origin through immunocyte and mucosa–specific receptor interactions. This site specificity of the mucosal immune response thereby significantly impedes the efficacy of systemic vaccination on local nasal respiratory mucosal immunity.

These concerns are amplified in light of multiple studies indicating that the nasal olfactory epithelium in particular is an early site of SARS-CoV-2 infection. Olfactory epithelium infection frequently manifests as a disturbance in the sense of smell and taste, which may be the only symptom in mild COVID-19 cases. Molecular and immunohistochemical studies demonstrate significantly higher levels of expression of the SARS-CoV-2 entry protein, ACE2, in olfactory sustentacular cells than even the respiratory epithelium.⁴ While the olfactory epithelium immune system is incompletely understood, it is conceivable that this primary neural tissue may also be relatively immune privileged and thus even further separated from the response to systemic vaccination than other airway mucosal surfaces. Unchecked by systemic humoral immune protection, SARS-CoV-2 entering the nasal airway may be able to infect and propagate there, shedding infectious virus asymptomatically for an unknown period of time.

These idiosyncratic features of mucosal immunity are highly germane to the current class of first-generation COVID-19 vaccines. One of the leading candidates from Johnson & Johnson leverages an Ad26 vector–based vaccine (adenovirus serotype 26) to express the SARS-CoV-2 spike protein. This strategy demonstrated robust neutralizing antibodies within bronchoalveolar lavage samples in preclinical nonhuman primate models (NHPs) after a single injection. While these results were interpreted as conferring robust systemic efficacy, low levels of virus were still detectable within some nasal swab samples. The authors of this study, published in Nature, concluded that “protection in both the upper and lower respiratory tracts will be required to prevent transmission and disease in humans.”⁵ Similarly, the NHP model of the Moderna mRNA-1273 vaccine demonstrated detectable viral RNA in the nasal swabs of several participants after SARS-CoV-2 challenge that exceeded that of the bronchoalveolar lavage samples.⁶

The findings of elevated nasal viral titers despite the effective prevention of COVID-19 have important implications for potential persistent transmission from vaccinated patients. The Centers for Disease Control and Prevention and the World Health Organization acknowledge that SARS-CoV-2 may be spread from asymptomatic individuals through respiratory droplets and airborne aerosols, based on a preponderance of epidemiologic data. From an otolaryngology perspective, multiple studies have now demonstrated that flexible and rigid nasal endoscopy, nasal debridement, and endonasal surgery can be associated with significant aerosol production.^7-10 These results have transformed the outpatient otolaryngology clinic, where provider N95 use and prolonged room resting are now recommended by multiple societal guidelines to prevent nosocomial transmission. While it is tempting to assume that widespread vaccination will alleviate these restrictions, the preclinical NHP findings suggest that this may be premature.

As the first generation of vaccines for COVID-19 is distributed and studied, we will be able to better understand the degree and duration of systemic efficacy in preventing COVID-19 infection. However, until viral titer endpoints are incorporated into vaccine trials and/or mucosal vaccines are developed, the possibility of asymptomatic nasal viral shedding from systemically vaccinated individuals should be considered. In light of subtotal vaccine efficacy, significant hesitancy levels, and waning immunity kinetics, it is clear that there will always be a substantial portion of our patient population that remains vulnerable to COVID-19. Even as we enthusiastically welcome the impending era of widespread COVID-19 vaccination programs, as otolaryngology providers we must remain vigilant in guarding against asymptomatic SARS-CoV-2 transmission in our clinics for the foreseeable future.

Author Contributions

Benjamin S. Bleier, concept, drafting, presentation; Murugappan Ramanathan Jr, drafting, presentation; Andrew P. Lane, drafting, presentation.

Disclosures

Competing interests: Benjamin S. Bleier has consultant relationships with Olympus, Medtronic, Karl Storz, Sinopsys, Baxter, Inquis Medical, and 3D Matrix and receives royalties from Theime. He holds patents for “Treatment of Sinusitis Through Modulation of Cell Membrane Pumps” (nonprovisional US patent assigned to Massachusetts Eye and Ear Infirmary), “Inhibition of Cystatins for the Treatment of Chronic Rhinosinusitis” (nonprovisional US patent), and “Methods of Delivery Pharmaceutical Agents” (US 13/561,998). Andrew P. Lane has served on an advisory board for Sanofi-Regeneron.

Sponsorships: None.

Funding source: None.