The predominant method of vaccine administration worldwide continues to be intramuscular injection. However, this approach has several drawbacks, including the need for cold-chain storage, the generation of biohazardous needle-waste, and the requirement for trained medical personnel to administer injections 1, 2. The World Health Organization and Coalition for Epidemic Preparedness Innovations (CEPI) have set a goal of producing a pandemic vaccine in 100 days [3], but the distribution logistics needed to administer injectable vaccines to the community would take months, even if the vaccine were produced in this timeframe. During the swine flu pandemic of 2009, Los Angeles County established 60 vaccination centers to administer influenza vaccines. At these sites, the average injection rate was 251 people per hour per center [4], demonstrating it would take several months to vaccinate the county’s nearly 10 million residents. During the initial rollout of the injectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, it took the United States from December of 2020 to August 2021 to administer at least one dose to 70% of the adult population, with a maximum vaccination rate of 3 million people/day [5]. This was done by repurposing athletic stadiums into vaccination sites, among other means [6]. Clearly, the major rate-limiting step to reaching protective levels of herd immunity in 2023 is not the manufacturing of injectable vaccines, but rather their administration. Next-generation vaccines that do not require cold-chain or healthcare networks for distribution may improve future pandemic vaccine rollout. With advances in modern transportation services, most items, including pharmaceutical prescriptions, can now be delivered efficiently to private homes in record time. If a room-temperature stable and self-administered vaccine, such as a tablet, could be distributed with the current infrastructure, pandemic vaccines could be delivered in a matter of weeks, not months, and without the burden of creating mass vaccination centers or the risk of exposure at these crowded sites. Furthermore, without the need for cold-chain distribution or trained medical professionals, vaccine deployment would also be more efficient in developing regions 1, 2. In fact, drones have already been deployed to deliver vaccines and other medical supplies in Scotland, Malawi, and communities that are hard to reach in the United States [7].

One of the benefits of an oral tablet vaccine is the delivery of the vaccine antigen to mucosal tissues and generation of mucosal immune responses. Most human pathogens infect through mucosal surfaces such as the respiratory and gastrointestinal tracts. Therefore, the presence of mucosal antibodies, generated by B cells, confers protection from many infections. Yet, injected vaccines do not elicit responses at these locations. Upon systemic antigen exposure, such as stimulated by injected vaccines, B cells are activated into antibody-secreting cells (ASCs) or plasmablasts that can enter the circulating immune system and secrete immunoglobulin G (IgG) or immunoglobulin A (IgA) in the blood. Alternatively, if the immune stimulus occurs at a mucosal site, these ASCs can express homing receptors, such as the mucosal-homing integrin α4β7, and traffic back to mucosal tissues (Figure 1a). Mucosal-residing plasmablasts can secrete dimeric IgA that transits through mucosal surfaces such as the nasal mucosa or upper respiratory tract while acquiring the secretory component to form secretory IgA (SIgA) (Figure 1a). Dimeric IgA has been shown to be more neutralizing than monomeric IgA or IgG, likely due to its increased valency 8, 9, 10. Additionally, the presence of the secretory component on SIgA protects the antibody from proteases and degradation, thereby increasing its stability in harsh mucosal environments 11, 12. Importantly, clinical studies have shown that ASCs generated from injected vaccination predominantly upregulate the lymph node-homing marker L-selectin (CD62L), while ASCs generated from mucosal vaccination upregulate the mucosal-homing integrin α4β7 [13], indicating that correlates of protection for mucosal vaccines may be different than those traditionally used for injected vaccines. Approved mucosal vaccines show the ability to induce a nasal IgA response, such as the intranasal influenza vaccine FluMist [14], or generate circulating IgA+ ASCs shortly after vaccination, such as the bivalent oral polio vaccine (bOPV) and oral cholera (Shanchol) vaccines 15, 16. These studies indicate IgA+ ASCs are likely a correlate of protection, making it a strong potential marker for assessing vaccine efficacy for other mucosal vaccines.

Here, we review next-generation oral recombinant vaccine solutions, with a particular focus on human and animal data that demonstrate measurable and protective mucosal immune responses. We highlight Vaxart’s oral tablet vaccination platform, which is comprised of nonreplicating oral recombinant adenovirus type-5 (rAd5) vector, designed to express the antigen of interest alongside a molecular double-stranded RNA adjuvant (Figure 1b), and is formulated into enterically coated tablets that can be self-administered and are room-temperature stable [17]. A key advantage of using a nonreplicating vaccine platform rather than an attenuated pathogen is the ability to respond quickly to a pandemic, using the exact same manufacturing process for every indication. The tableting procedure is a nonsterile process that takes less than two days and does not add significant amount of time to the overall vaccine production process [17]. In comparison, sterile-fill and finish for needle-based vaccines is subject to specialized medical-grade glass supply chain issues as observed during early COVID-19 vaccine development [18] and complicated sterility testing to ensure batch integrity. In the intestinal ileum, it is thought that rAd5 is released from the tablets and taken up by enterocytes where the antigen of interest is expressed alongside the dsRNA adjuvant to trigger innate immune signaling. This vaccine platform has been tested in several phase-I/-II clinical trials for influenza, norovirus, and SARS-CoV-2 19••, 20, 21••, 22, 23, 24, 25, 26, 27• and in preclinical animal models 28, 29, 30, 31, 32, 33, 34, 35••. In addition to being well-tolerated, highly immunogenic, and easily distributed, this mucosal vaccine may also have the capability of reducing pathogen transmission in the community.