We have initiated development of a mucosal Hepatitis B vaccine using GMP Hepatitis B Surface Antigen (HBsAP) in nanoemulsion adjuvant. Studies are undertaken to test immunogenicity and toxicity first in rodents and then in primates. These will address potential long-term adverse reactions such as autoimmunity. A small-scale Phase I trial will subsequently be conducted to evaluate toxicity and immunogenicity of the vaccine in humans.
A major goal of the Grand Challenges in Global Health for disease prevention in the developing world is the availability of effective vaccines. Unfortunately, almost all current vaccines require refrigeration and must be given by multiple injections, making them unsuitable for mass vaccination in most developing countries. In addition, many vaccines require an adjuvant, or an immune stimulant, as a co-factor to induce an effective immune response. This material also creates stability issues and can cause toxicity, thereby complicating both the formulation and development of vaccines. While few of the existing mucosal vaccines are more effective and easier to administer than needle-based approaches, the adjuvants in some mucosal vaccines have been associated with adverse reactions, such as autoimmunity.
We have recently discovered that when either whole enveloped virus or a recombinant protein antigen is simply mixed with nanoemulsion and placed into the nose, the nanoemulsion serves as a potent adjuvant, producing both systemic and mucosal immunity and cell-mediated immune responses. This is accomplished without the need for toxins or additional immuno-stimulants through a process that appears to involve dendritic cell uptake of the nanoemulsion/antigen mixture. The mechanism depends on the small size and high potential energy of the nanoemulsions droplets, and the efficiency by which this material is endocytosed by dendritic cells. Nanoemulsion-based mucosal vaccines appear to require fewer immunizations to achieve effective immune responses than traditional vaccines. The nanoemulsion even stabilizes the antigen, and, because it is antimicrobial, it may alleviate the need for other preservatives or refrigeration and can prevent accidental cross-contamination between vaccinees. Therefore, we expect that nanoemulsions will provide a safe and effective adjuvant for mucosal vaccines that are easily produced, even in underdeveloped areas, and require no special storage.
To develop this technology, we are performing preclinical efficacy toxicology studies as well as human toxicological studies for a prototype Hepatitis B vaccine. A Hepatitis B vaccine was chosen because it could prevent critical problems in the developing world and involves disease transmission across mucosal membranes; so a mucosal vaccine may have unique benefits. As a source of antigen, we use the approved recombinant Hepatitis B vaccine and mix it in a nanoemulsion vehicle. In later-stage clinical trials, this would allow for the direct comparison between an approved injectable vaccine and a nanoemulsion-based mucosal vaccine. Different means of nasal administration will be evaluated in order to assure an approach that makes sense in developing countries.
This work has been supported by the Bill & Melinda Gates Foundation under the Grand Challenges in Global Health Initiative.