title: Immunogenicity differences of a 15-valent pneumococcal polysaccharide conjugate vaccine (PCV15) based on vaccine dose, route of immunization and mouse strain.
abstract: Pneumococcal disease continues to be a medical need even with very effective vaccines on the market. Globally, there are extensive research efforts to improve serotype coverage with novel vaccines; therefore, conducting preclinical studies in different animal models becomes essential. The work presented herein focuses on evaluating a 15-valent pneumococcal conjugate vaccine (PCV15) in mice. Initially we evaluated several doses of PCV15 in Balb/c mice. The optimal vaccine dose was determined to be 0.4μg per pneumococcal polysaccharide (PS) (0.8μg of 6B) for subsequent studies. This PS dose was chosen for PCV evaluation in mice based on antibody levels determined by multiplexed electrochemiluminescent (ECL) assays, T-cell responses following in vitro stimulation with CRM197 peptides and protection from pneumococcal challenge. We then selected four mouse strains for evaluation: Balb/c, C3H/HeN, CD1 and Swiss Webster (SW), immunized with PCV15 by either intraperitoneal (IP) or intramuscular (IM) routes. We assessed IgG responses by ECL assays and functional antibody activity by multiplexed opsonophagocytic assays (MOPA). Every mouse strain evaluated responded to all 15 serotypes contained in the vaccine. Mice tended to have lower responses to serotypes 6B, 23F and 33F. The IP route of immunization resulted in higher antibody titers for most serotypes in Balb/c, C3H and SW. CD1 mice tended to respond similarly for most serotypes, regardless of route of immunization. Similar trends were observed with the four mouse strains when evaluating functional antibody activity. Given the differences in antibody responses based on mouse strain and route of immunization, it is critical to evaluate pneumococcal vaccines in multiple animal models to determine the optimal formulation before moving to clinical trials.
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Ivette
authors.initials: I
authors.lastname: Caro-Aguilar
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Lani
authors.initials: L
authors.lastname: Indrawati
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Kaufhold
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Gaunt
authors.affiliation: Non-clinical Statistics, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Bioprocess Research & Development, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Nawrocki
authors.affiliation: Bioprocess Research & Development, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giovarelli
authors.affiliation: Bioprocess Research & Development, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Winters
authors.affiliation: Bioprocess Research & Development, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Smith
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Department of Infectious Diseases/Vaccines, MRL (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address: julie_skinner@merck.com.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Skinner
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D022242:Pneumococcal Vaccines / Q000008:administration & dosage* / Q000138:chemical synthesis; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D065288:Serogroup; D013045:Species Specificity; D013296:Streptococcus pneumoniae / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014611:Vaccination; D018074:Vaccines, Conjugate
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial; D018074:Vaccines, Conjugate; C028581:CRM197 (non-toxic variant of diphtheria toxin)
keywords: Immunogenicity; Mouse model; Pneumococcal vaccine