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1.
Vaccine ; 39(30): 4231-4237, 2021 07 05.
Article in English | MEDLINE | ID: mdl-34074546

ABSTRACT

Invasive pneumococcal disease (IPD) is responsible for serious illnesses such as bacteremia, sepsis, meningitis, and pneumonia in young children, older adults, and persons with immunocompromising conditions and often leads to death. Although the most recent pneumococcal conjugate vaccines (PCVs) have been designed to target serotypes identified as the primary causative agents of IPD, the epidemiological landscape continues to change stressing the need to develop new PCVs. We have developed an investigational 24-valent PCV (PCV24) including serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F all conjugated to CRM197 and evaluated this vaccine in adult monkeys. PCV24 was shown to be immunogenic and induced functional antibody for all vaccine serotypes. Of the serotypes common to PCV13 and V114 (PCV15), PCV24 had a similar immunogenic response with the exceptions of 23F which had higher IgG GMCs for PCV13 and V114, and 7F which had higher GMCs for PCV13. Functional antibody responses were similar for the serotypes in common between PCV24, PCV13 and V114 vaccines, with the exception of serotype 7F which was greater for PCV13. Overall, this study shows that PCV24 provided similar immunogenicity as the lower valent vaccines in adult monkeys with no apparent serotype interference. In addition, PCV24 also provided protection against pneumococcal infection in a mouse challenge model.


Subject(s)
Pneumococcal Infections , Pneumococcal Vaccines , Aged , Animals , Antibodies, Bacterial , Child, Preschool , Haplorhini , Humans , Infant , Mice , Pneumococcal Infections/prevention & control , Vaccines, Conjugate
2.
Pediatr Infect Dis J ; 39(1): 70-77, 2020 01.
Article in English | MEDLINE | ID: mdl-31725555

ABSTRACT

BACKGROUND: Evaluation of a pneumococcal conjugate vaccine (PCV) in an animal model provides an initial assessment of the performance of the vaccine prior to evaluation in humans. Cost, availability, study duration, cross-reactivity and applicability to humans are several factors which contribute to animal model selection. PCV15 is an investigational 15-valent PCV which includes capsular polysaccharides from pneumococcal serotypes (ST) 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F all individually conjugated to cross-reactive material 197 (CRM197). METHODS: Immunogenicity of PCV15 was evaluated in infant rhesus macaques (IRM), adult New Zealand white rabbits (NZWR) and CD1 mice using multiplexed pneumococcal electrochemiluminescent (Pn ECL) assay to measure serotype-specific IgG antibodies, multiplexed opsonophagocytosis assay (MOPA) to measure serotype-specific functional antibody responses and bacterial challenge in mice to evaluate protection against a lethal dose of S. pneumoniae. RESULTS: PCV15 was immunogenic and induced both IgG and functional antibodies to all 15 vaccine serotypes in all animal species evaluated. PCV15 also protected mice from S. pneumoniae serotype 14 intraperitoneal challenge. Opsonophagocytosis assay (OPA) titers measured from sera of human infants vaccinated with PCV15 in a Phase 2 clinical trial showed a good correlation with that observed in IRM (rs=0.69, P=0.006), a medium correlation with that of rabbits (rs=0.49, P=0.06), and no correlation with that of mice (rs=0.04, P=0.89). In contrast, there was no correlation in serum IgG levels between human infants and animal models. CONCLUSIONS: These results demonstrate that PCV15 is immunogenic across multiple animal species, with IRM and human infants showing the best correlation for OPA responses.


Subject(s)
Immunogenicity, Vaccine , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/immunology , Streptococcus pneumoniae/immunology , Vaccines, Conjugate/immunology , Animals , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Cell Line, Tumor , Disease Models, Animal , Heptavalent Pneumococcal Conjugate Vaccine/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Mice
3.
Vaccine ; 35(6): 865-872, 2017 02 07.
Article in English | MEDLINE | ID: mdl-28087148

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.


Subject(s)
Antibodies, Bacterial/biosynthesis , Immunoglobulin G/biosynthesis , Pneumococcal Vaccines/administration & dosage , Pneumonia, Pneumococcal/prevention & control , Streptococcus pneumoniae/drug effects , Vaccination , Animals , Bacterial Proteins/pharmacology , Disease Models, Animal , Dose-Response Relationship, Immunologic , Drug Evaluation, Preclinical , Female , Humans , Injections, Intramuscular , Injections, Intraperitoneal , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred Strains , Pneumococcal Vaccines/chemical synthesis , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/microbiology , Polysaccharides, Bacterial/administration & dosage , Polysaccharides, Bacterial/chemistry , Polysaccharides, Bacterial/immunology , Serogroup , Species Specificity , Streptococcus pneumoniae/chemistry , Streptococcus pneumoniae/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Vaccines, Conjugate
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