by Gertrud U. Rey
Norovirus is the most common food-borne virus and the leading cause of gastroenteritis globally. Despite an urgent need, there are currently no licensed vaccines to prevent norovirus-induced illness. Nevertheless, recent developments in this field have led to remarkable and promising new advances.
A phase 1b clinical trial has revealed that a norovirus vaccine candidate is safe and elicits mucosal immunity in older adults. The vaccine is an orally-administered tablet, which contains a recombinant adenovirus vector with two main components: an inserted gene that encodes the VP1 antigen of the GI.1 norovirus genotype, and a double-stranded RNA (dsRNA). The tablet is coated with a polymer that keeps it stable in the acidic environment of the stomach until it reaches the more alkaline conditions of the small intestine where the medication is absorbed. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Once inside the small intestine, the vaccine vector “infects” the local cells and serves as a code for cellular proteins to synthesize the norovirus VP1 protein from the inserted gene. The VP1 protein then acts as an antigen to prime the immune system to recognize the GI.1 genotype of norovirus if it infects the body at a later time. Because it is the major capsid protein of noroviruses, VP1 is crucial for norovirus infectivity and antigenicity, and is thus a key target for vaccines and antiviral therapies. The dsRNA component of the vaccine acts as an adjuvant because it binds the innate immunity-associated toll-like receptor 3 (TLR-3), a dsRNA-sensing protein that is abundant on intestinal cells. The binding of the dsRNA to TLR-3 triggers a signaling cascade that eventually establishes an antiviral immune response.
The clinical trial enrolled sixty-five US-resident participants between 55 and 80 years of age, and was structured as a randomized, placebo-controlled, and double-blinded study. In other words, the participants were randomly assigned to receive the experimental vaccine or a placebo control. Furthermore, both the participants and investigators were unaware of whether any particular participant received the vaccine or a placebo (i.e., both groups were “blinded”) in order to reduce outcome bias. The vaccine was administered orally and given in two doses spaced one month apart.
The investigators evaluated the safety and tolerability of the vaccine by recording post-vaccination symptoms. They also did a preliminary assessment of vaccine efficacy by measuring the levels of IgG and IgA antibodies in the serum and saliva. IgG antibodies provide the majority of systemic antibody-based immunity. IgA antibodies also circulate systemically, but are mostly prevalent in mucosal surfaces where they defend against invasion by inhaled and ingested pathogens.
The basic findings of the study were as follows:
- The vaccine was generally safe and well tolerated;
- The two main post-vaccination symptoms – headache and fatigue – were reported at similar rates in the experimental and placebo groups, suggesting that the norovirus vaccine did not cause these symptoms;
- Norovirus vaccine recipients had increased levels of VP1-specific IgG and IgA antibodies in the serum compared to their baseline levels and those in placebo recipients, with no significant differences observed between age groups; and
- Norovirus vaccine recipients had increased levels of VP1-specific IgA antibodies in the saliva and nasal mucosa compared to their baseline levels and those in placebo recipients, with no significant differences observed between age groups.
These findings suggest that vaccination with the experimental norovirus vaccine tablet is safe and induces both systemic and mucosal immune responses in all age groups tested.
The authors of the study are careful to note several limitations. The cohort size was small and the vaccine was only assessed in older adults, using a vaccine that only targets a single genotype. Additional work is needed to evaluate the efficacy of the vaccine in larger cohorts consisting of more wide-ranging age groups. Nevertheless, it is encouraging to see such positive results in older people who are generally less responsive to vaccination because they have weakened immune systems. A larger phase 2 trial is currently underway to evaluate the efficacy of an oral vaccine directed against norovirus GI.1 (the genotype encoded in the presently tested vaccine candidate) and GII.4, the genotype that causes a majority of norovirus outbreaks. The trial includes adults ranging in age from 18 to 80 years.
An orally-delivered norovirus vaccine tablet would be ideal for several reasons. First, it is thermostable and thus does not require cold storage. Second, it can be self-administered without the need for a trained professional. Third, its apparent ability to induce norovirus-specific antibodies in the saliva is optimal when considering that norovirus is transmitted by ingestion. Previous work has shown that the presence of norovirus-specific antibodies in the saliva correlates with immunity, which has the potential to inhibit infection, viral shedding, and transmission. I look forward to reading about improvements of this vaccine and hope that it will be approved for use in the near future.