At Issue

Which norovirus vaccine candidate or approach holds the most promise?

Experts are developing and testing numerous vaccine candidates against norovirus, which causes hundreds of millions of infections each year worldwide and is seen as a top target for vaccine research. Infectious Disease News asked Xavier Sáez-Llorens, MD, principal investigator for Cevaxin, a vaccines and clinical research center in Panama, which norovirus vaccine or vaccine approach holds the most promise.

Norovirus infection is a leading cause of foodborne illness and acute gastroenteritis worldwide. It particularly affects children aged younger than 5 years, elderly persons, and individuals suffering crowding, such as travelers and military personnel. A rapidly evolving genetic diversity, short-term natural immune response, homotypic immunity to infection, absence of a well-established correlate of protection, lack of a suitable animal model and the uncertain burden of disease and cost estimates are all relevant challenges for vaccine development.

Xavier Sáez-Llorens, MD
Xavier
Sáez-Llorens

Several candidate vaccines are currently in early clinical phases, including viruslike particles (VLPs), P particles and recombinant replicon particles using viral vectors. Delivery strategies of these vaccines in humans include administration by various routes (eg, oral, intranasal, parenteral), with or without adjuvants, and a combination of antigens to prevent other infections concomitantly (eg, rotavirus, hepatitis E, enterovirus 71). The bivalent GI.1/GII.4 VLP-based intramuscular vaccine (TAK-214, Takeda) is the most advanced candidate in research trials at the present time.

Two adult phase 1 studies demonstrated that this vaccine was safe, well tolerated and elicited good immune responses. A phase 2 trial, also in adults, randomly assigned to receive intramuscular saline (placebo) or vaccine formulations containing 15 or 50 mg of GI.1/50 mg GII.4 VLPs, confirmed the safety and immunogenicity of this candidate. Because norovirus can cause frequent diarrheal episodes with dehydration, hospitalization and even death in very young infants, several Latin American investigators from Panama and Colombia decided to participate in a pediatric, double-blind, randomized, phase 2 dose-finding study of this vaccine, that evaluated formulations containing 15/15, 15/50, 50/50 or 50/150 mg doses of GI.1/GII.4c genotype VLPS, adjuvanted with 0.5 mg Al (OH)3. Two groups of infants received either two or three intramuscular doses, respectively, of the different preparations on days 56, 84 and 140.

All candidates were well tolerated, exhibited clinically acceptable reactogenicity profiles in infants and children and were associated with high antibody responses observed after two doses 8 weeks apart, with a further increase after the third dose 8 weeks later. Based on preliminary immunogenicity results and boosting effects, the dose selection for the phase 3 trial in children aged 6 months to 2 years, will probably be two doses of the 50/150 mg vaccine formulation, but a final decision has not been made by Takeda. It is important to mention, however, that given the busy immunization schedule of pediatric subjects aged younger than 2 years, an oral vaccine, rather than an intramuscular vaccine, will be preferred by parents and physicians.

Disclosure: Sáez-Llorens reports that his research organization, Cevaxin, has received a grant from Takeda.

Experts are developing and testing numerous vaccine candidates against norovirus, which causes hundreds of millions of infections each year worldwide and is seen as a top target for vaccine research. Infectious Disease News asked Xavier Sáez-Llorens, MD, principal investigator for Cevaxin, a vaccines and clinical research center in Panama, which norovirus vaccine or vaccine approach holds the most promise.

Norovirus infection is a leading cause of foodborne illness and acute gastroenteritis worldwide. It particularly affects children aged younger than 5 years, elderly persons, and individuals suffering crowding, such as travelers and military personnel. A rapidly evolving genetic diversity, short-term natural immune response, homotypic immunity to infection, absence of a well-established correlate of protection, lack of a suitable animal model and the uncertain burden of disease and cost estimates are all relevant challenges for vaccine development.

Xavier Sáez-Llorens, MD
Xavier
Sáez-Llorens

Several candidate vaccines are currently in early clinical phases, including viruslike particles (VLPs), P particles and recombinant replicon particles using viral vectors. Delivery strategies of these vaccines in humans include administration by various routes (eg, oral, intranasal, parenteral), with or without adjuvants, and a combination of antigens to prevent other infections concomitantly (eg, rotavirus, hepatitis E, enterovirus 71). The bivalent GI.1/GII.4 VLP-based intramuscular vaccine (TAK-214, Takeda) is the most advanced candidate in research trials at the present time.

Two adult phase 1 studies demonstrated that this vaccine was safe, well tolerated and elicited good immune responses. A phase 2 trial, also in adults, randomly assigned to receive intramuscular saline (placebo) or vaccine formulations containing 15 or 50 mg of GI.1/50 mg GII.4 VLPs, confirmed the safety and immunogenicity of this candidate. Because norovirus can cause frequent diarrheal episodes with dehydration, hospitalization and even death in very young infants, several Latin American investigators from Panama and Colombia decided to participate in a pediatric, double-blind, randomized, phase 2 dose-finding study of this vaccine, that evaluated formulations containing 15/15, 15/50, 50/50 or 50/150 mg doses of GI.1/GII.4c genotype VLPS, adjuvanted with 0.5 mg Al (OH)3. Two groups of infants received either two or three intramuscular doses, respectively, of the different preparations on days 56, 84 and 140.

All candidates were well tolerated, exhibited clinically acceptable reactogenicity profiles in infants and children and were associated with high antibody responses observed after two doses 8 weeks apart, with a further increase after the third dose 8 weeks later. Based on preliminary immunogenicity results and boosting effects, the dose selection for the phase 3 trial in children aged 6 months to 2 years, will probably be two doses of the 50/150 mg vaccine formulation, but a final decision has not been made by Takeda. It is important to mention, however, that given the busy immunization schedule of pediatric subjects aged younger than 2 years, an oral vaccine, rather than an intramuscular vaccine, will be preferred by parents and physicians.

Disclosure: Sáez-Llorens reports that his research organization, Cevaxin, has received a grant from Takeda.