Drop the Needle; A Temperature Stable Oral Tablet Vaccine Is Protective against Respiratory Viral Pathogens

Abstract

To effectively combat emerging infections and prevent future pandemics, next generation vaccines must be developed quickly, manufactured rapidly, and most critically, administered easily. Next generation vaccines need innovative approaches that prevent infection, severe disease, and reduce community transmission of respiratory pathogens such as influenza and SARS-CoV-2. Here we review an oral vaccine tablet that can be manufactured and released in less than 16 weeks of antigen design and deployed without the need for cold chain. The oral Ad5 modular vaccine platform utilizes a non-replicating adenoviral vector (rAd5) containing a novel molecular TLR3 adjuvant that is delivered by tablet, not by needle. This enterically coated, room temperature-stable vaccine tablet elicits robust antigen-specific IgA in the gastrointestinal and respiratory tracts and upregulates mucosal homing adhesion molecules on circulating B and T cells. Several influenza antigens have been tested using this novel vaccine approach and demonstrated efficacy in both preclinical animal models and in phase I/II clinical trials, including in a human challenge study. This oral rAd5 vaccine platform technology offers a promising new avenue for aiding in rapid pandemic preparedness and equitable worldwide vaccine distribution.

Keywords: IgA; adenoviral vector vaccine; antibody-secreting cells; mucosal immune response; oral vaccines; vaccine tablet.

Figure 1

Next generation vaccine production, manufacturing, and distribution timelines during a pandemic. (A) Non-replicating recombinant adenovirus serotype 5 (rAd5) vaccine constructs can be developed and used in preclinical testing in as little as three weeks. Large scale manufacturing and release timelines for rAd-based vaccines are comparable and can be completed within 9 weeks, as demonstrated during the 2020 pandemic (S. Gilbert, personal communication, 28 October 2021). mRNA-based vaccines have the shortest development and manufacturing timelines; however, these formulations are the most difficult to transport and store [18,23]. (B) An oral tablet rAd5 vaccine that is room temperature-stable can be shipped without cold chain and does not need to be administered by trained health care professionals. Distribution of an oral vaccine can exponentially speed up vaccine rollout compared to injected vaccines, especially in areas with considerably fewer resources, as tablets can be shipped directly to individuals and self-administered. Traditional needle-based immunization approaches have an inherent distribution bottleneck due to temperature constraints for shipping and storage and the need for health care professionals to administer the vaccines. Administering needle-based vaccines seems to be the greatest bottleneck and can take more than 6 months, even with substantial investment in infrastructure.

Figure 2

Working model of oral rAd5 vaccine tablet, illustrating how antigen delivery to the small intestine generates protective mucosal immune responses. The non-replicating rAd5 vector contains both the vaccine antigen transgene and the molecular TLR3 adjuvant, which are delivered together to epithelial and resident immune cells. Once released in the gut ileum, the tablet’s enteric coating dissolves and releases rAd5 into the lumen. Following translation of the transgene, the vaccine protein antigen can be displayed on target cells in native confirmation or cross-presented to T cells as peptides on MHC I and II. Constantly sampling the intestinal lumen are other antigen-presenting immune cells, such as dendritic cells (DCs), that can display non-self antigens to naïve T cells and drive T follicular (TfH) expansion. TfH cells provide co-stimulation that enhances B cell differentiation, maturation, and class-switch recombination to IgA-expressing activated B cells. Activated B cells mature into IgA-secreting plasmablasts and enter the lymph and blood, where they traffic to lymphoid tissues and mucosal sites. Following oral vaccination, circulating IgA antibody-secreting cells upregulate the mucosal homing marker α4β7+, traffic to the respiratory tract, and secrete IgA. IgA transcytosis through the epithelial layer is mediated by the polymeric Ig receptor (pIgR) and released into the airway. Resident T cells may also recognize vaccine antigens displayed on the surface of gut epithelial cells or dendritic cells and elicit effector T cell maturation. These effector T cells can provide additional mucosal protection by identifying naturally infected cells and releasing effector molecules, such as IFNγ and granzyme (GzmB), in response to infection.