Oral tablet vaccination against SARS-CoV-2 spike boosts cross-reactive serum and mucosal neutralizing antibodies following mRNA vaccination: a phase 2 clinical trial

Abstract

Abstract Current SARS-CoV-2 intramuscular vaccines do not induce the breadth of immunity needed to halt the development of new variants. New strategies that elicit immunity at the site of infection could induce cross-reactive mucosal responses that decrease transmission. We developed a room-temperature stable oral tablet vaccine composed of recombinant adenovirus type 5 expressing the spike gene of SARS-CoV-2. In an open label phase 2 clinical trial (NCT05067933), 66 subjects, either naïve or previously mRNA vaccinated, received 2 doses of a low or a high dose 28 days apart. The vaccine was well tolerated with a benign safety profile. Among previously vaccinated subjects, oral tablet vaccination was able to boost serum IgG and IgA at 29 and 57 days post-vaccination. The serum neutralizing antibodies increased 1.6-fold, from 481 AU/ml to 778 AU/ml at Day 57. The subjects with lower starting titers had greater increases after oral boosting. Most subjects in the vaccinated cohorts had an increase in SARS-CoV-2 IgA in the nose or saliva. This mucosal IgA was not only cross-reactive against SARS-CoV-2 variants but also SARS-CoV-1 and MERS. These samples demonstrated surrogate neutralizing activity against both Wuhan and omicron BA4/5, despite the vaccine expressing Wuhan antigens, highlighting the ability of mucosal vaccination to elicit cross-reactive responses. Overall, this vaccine was safe and well tolerated. It induced cross-reactive immunity in both the serum and more importantly, in the mucosa, the site of infection. This offers an ideal platform for boosting immune responses that could decrease transmission rates and extend protection to emerging variants. It also offers unique advantages in distribution to curb future pandemics.