Our group is interested in improving the efficacy of vaccines by developing new adjuvants and better vaccine adjuvant formulations. Adjuvants (the term is derived from the Latin word adjuvare = to help) are substances added to vaccines to enhance the immune response and to induce the type of immune response that provided optimal protection following vaccination. The most commonly used adjuvants in human vaccines are aluminum-containing adjuvants, but other adjuvants have recently been introduced in licensed vaccines. Vaccines for use in animals contain a broad variety of adjuvants including aluminum adjuvants, oil emulsions, liposomes and polymers. We are investigating how aluminum-containing adjuvants work and ways to improve the efficacy of these adjuvants. A second project is focused on the development of completely new adjuvants based on plant-derived nanoparticles. A third project in the lab is aimed at identifying genetic factors that influence the immune response to vaccines. This could provide insight into the mechanisms by which adjuvants enhance the immune response.
There are two types of aluminum adjuvants, aluminum hydroxide adjuvant and aluminum phosphate adjuvant. They differ in surface charge and in structure which affects their interaction with vaccine antigens and their biological effects. Aluminum adjuvants are present in many vaccines including diphtheria-tetanus-acellular pertussis (DTaP), hepatitis B, meningococcal and pneumococcal vaccines and the human papilloma virus (HPV) vaccines. Aluminum adjuvants adsorb vaccine antigens via electrostatic and ligand exchange mechanisms. The degree and strength of adsorption can be controlled by the choice of aluminum adjuvant, the phosphate content and ionic strength of the buffer and by conjugating antigens with phosphate groups. The role of adsorption in enhancing the immune response varies and depends on the antigen and the dose of antigen. Aluminum adjuvants induce inflammation at the injection site following intramuscular or subcutaneous injection. The inflammation is thought to be necessary for the stimulation of the immune response by recruiting antigen-presenting cells, and is generally not harmful. In a detailed study of the kinetics of the inflammatory response, we discovered differences in the inflammation between primary and secondary (booster) immunizations. Neutrophils arrive early and in large numbers at the injection site, but they do not appear to be necessary for the stimulation of the immune response. The large positively charged adsorptive surface of aluminum adjuvants allows adsorption of negatively charged immunomodulators such as TLR agonists as well as antigen. This enhances the immune response while preventing unwanted systemic effects.
- Lu F, Mosley YC, Brown D, Carmichael B, HogenEsch H (2019) Formulation of aluminum hydroxide adjuvant with TLR agonists poly(I:C) and CpG enhances the magnitude and avidity of the humoral immune response. Vaccine, 37:1945-1953.HogenEsch H, O'Hagan DT, Fox CB
- (2018) Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. Npj Vaccines, 3:51.
- HogenEsch H (2013) Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol, 3:406.
- Lu F, HogenEsch H (2013) Kinetics of inflammation following injection of aluminum-adjuvanted vaccines. Vaccine, 31: 3979-3986.
Aluminum adjuvants have a few limitations including their susceptibility to freezing, the persistence of inflammation at the injection site for months, and sometimes negative effects on the stability of adsorbed antigens. We recently discovered that nanoparticles derived from a variety of sweet corn, modified to give them a positive surface charge, can be used as vaccine adjuvants. The 70-80 nm particles, termed Nano-11, are readily taken up by dendritic cells and activate dendritic cells to increase the expression of CD80 and CD86 and to secrete IL-1β. In vivo studies indicate that the nanoparticles are preferentially taken up by dendritic cells migrating to the draining lymph nodes. Nano-11 enhanced the immune response to different protein antigens in mice, pigs and horses. Advantages over currently licensed adjuvants include stability, biodegradability and low cost. We are presently investigating the immunobiology of these nanoparticles and exploring the possibility of intradermal and mucosal vaccination using Nano-11.
- Lu F, Mencia A, Bi L, Taylor A, Yao Y, HogenEsch H (2015) Dendrimer-like alpha-D-glucan nanoparticles activate dendritic cells and are effective vaccine adjuvants. J Control Release, 204: 51-59.
- Lu F, Mosley Y, Rosales RR, Carmichael BE, Elesela S, Yao Y, HogenEsch H (2017) Alpha-D-glucan nanoparticulate adjuvant induces a transient inflammatory response at the injection site and targets antigen to migratory dendritic cells. Npj Vaccines, 2:4.
Genetics of the immune response to vaccines
The genetic make-up of animals and people influences the magnitude and quality of the immune response to vaccines. Identifying the genes associated with the differences in the immune response can help in understanding the mechanisms that drive the immune response and ways to improve vaccine performance. We recently conducted a study in mice in which we injected 28 different inbred strains with a diphtheria-tetanus-acellular pertussis (DTaP) vaccine. This childhood vaccine has been very effective in reducing the incidence of diphtheria, tetanus and pertussis, however, a recent resurgence of pertussis has raised concerns about the longevity of the protection provided by the vaccine. As expected, there were significant differences between genetically different mice in the magnitude and longevity of the antibody responses to the vaccine. An important observation was that the longevity of the antibody response to different vaccine antigens was significantly correlated suggesting that this is largely determined by antigen-independent mechanisms in the vaccine formulation such as the aluminum adjuvant in the DTaP vaccine.
- Mosley YC, Radder JE, HogenEsch H (2019) Genetic variation in the magnitude and longevity of the IgG subclass response to a Diphtheria-Tetanus-acellular Pertussis (DTaP) vaccine in mice.Vaccines, 7:124.
- Mosley YYC, Radder JE, Berndt A, HogenEsch H (2017) Genome-wide association mapping of the antibody response to diphtheria-tetanus-acellular pertussis vaccine in mice. J Infectious Dis, 215:466-474.