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Principal Investigator: Peter B. Gilbert
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $536,488
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY (See instructions):
Safe and efficacious vaccines are needed to massively reduce the economic and human health costs of
HIV-1/AIDS, dengue, malaria, and COVID-19. This goal has been hindered by the genetic diversity of the
etiological pathogens. Randomized, controlled trials that rigorously assess the efficacy of candidate
vaccines to prevent infection and/or disease caused by these pathogens are a core research platform for
improving vaccines. Moreover, randomized efficacy trials of broadly neutralizing monoclonal antibody
(bnAb) regimens aid vaccine development. This project develops statistical methods for vaccine and bnAb
prevention efficacy trials, with purpose lo rigorously characterize multiple types of distinct and
complementary "immune correlates," which are critical tools for driving the iterative research process for
improving vaccines. Aim 1 develops methods for assessing immune markers measured over lime as
correlates of instantaneous risk of acquisition of HIV-1 or SARS-CoV-2 (of any strain or with a strain with
a particular feature such as an amino acid (AA) sequence or neutralization phenotype) in (a) HIV-1 and
COVID-19 vaccine and (b) HIV-1 bnAb efficacy trials. Aim 2 develops methods for assessing immune
markers measured by a fixed time point post-vaccination in HIV-1, dengue, malaria, and COVID-19
vaccine efficacy (VE) trials as multiple types of correlates of protection: (a) an estimated optimal surrogate
a summary marker combining information from all markers that best predicts overall or feature-specific
outcome; (b) a correlate of VE la marker that modifies VE, studied via the statistical frameworks principal
stratification, controlled causal effects, and stochastic interventional causal effects. Aim 3 develops
dynamic recurrent event models for assessing (a) malaria VE against overall and circumsporozoite protein
(CSP) AA-specific malaria infection and disease, and (b} how CSP AA-specific malaria risk depends on
prior malaria infections and vaccination. Aim 4 develops causal methods for assessing vaccine and bnAb
efficacy to prevent (a) overall and (b) feature-specific HIV-1 acquisition in study populations defined by
certain patterns of pre-exposure prophylaxis use. The methods are developed with application lo 14
recently completed or ongoing VE trials (4 for HIV-1, 2 for dengue, 2 for malaria, 6 for COVID-19) and 2
HIV-1 bnAb efficacy trials. Collectively, the aims advance development of immune correlates based on
both immune marker data and pathogen genetic sequence/immunophenotype data.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><AIDS><Accounting><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Address><Advanced Development><Amino Acid Sequence><Amino Acids><Antibodies><Automobile Driving><Biological Markers><Blood><Blood Reticuloendothelial System><Blood Serum><Breakbone Fever Virus><COVID-19><COVID-19 vaccine><COVID-19 virus><COVID19 virus><CV-19><Causality><Clinical><Clinical Treatment Moab><Clinical Trials><CoV-2><CoV2><Coronavirus Infectious Disease 2019><DENV><DENV vaccine><Data><Data Analyses><Data Analysis><Dengue><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus vaccine><Development><Disease><Disorder><Drug Kinetics><Dryness><Economics><Etiology><Event><Failure><Genetic><Genetic Diversity><Genetic Variation><Goals><HIV Vaccine Trials Network><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HVTN><Health><Health Care Costs><Health Costs><Healthcare Costs><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Immune><Immune Markers><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Markers><Immunologic Subtyping><Immunological><Immunological response><Immunologically><Immunologics><Immunophenotyping><Individual><Infection><Infection prevention><Instruction><Intervention><Intervention Strategies><Investigation><Joints><Limes><Malaria><Malaria Vaccines><Malarial Vaccines><Measurement><Measures><Mediating><Methods><Modality><Modeling><Modern Man><Monoclonal Antibodies><Outcome><P falciparum><P. falciparum><P.falciparum><Paludism><Pattern><Pharmacokinetics><Phenotype><Plasmodium Infections><Plasmodium falciparum><Population><PrEP><Prevent infection><Preventative vaccine><Prevention><Preventive vaccine><Primary Protein Structure><Prophylactic vaccine><Proportional Hazards Models><Protein C><Randomized><Randomized, Controlled Trials><Recurrence><Recurrent><Regimen><Research><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccine><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Spottings><Statistical Methods><Stratification><Surrogate End Points><Surrogate Endpoint><Time><Vaccination><Vaccines><Viral><Virus><Wuhan coronavirus><aminoacid><bio-markers><biologic marker><biomarker><causal diagram><causal model><causation><circumsporozoite protein><coronavirus disease 2019><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cs protein><data interpretation><deep sequencing><design><designing><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease causation><driving><economic><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><efficacy trial><evaluate efficacy><examine efficacy><hCoV19><host response><immune response to vaccination><immune response to vaccines><immune system response><immune-based biomarkers><immunological biomarkers><immunological markers><immunophenotype><immunoresponse><improved><innovate><innovation><innovative><insight><interest><interventional strategy><mAbs><malaria infection><malaria-infected><malarial infection><monoclonal Abs><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing mAb><neutralizing monoclonal antibodies><pathogen><peptide aminoacid sequence><peptide sequence><pre-exposure prophylaxis><prevent><preventing><prevention efficacy trial><process improvement><protein aminoacid sequence><protein sequence><randomisation><randomization><randomized control trial><randomly assigned><response biomarker><response markers><statistic methods><study population><tool><vaccination study><vaccination trial><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against DENV><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against dengue><vaccine antibodies><vaccine associated immune response><vaccine candidate><vaccine candidate against dengue><vaccine candidates against SARS-CoV-2><vaccine development><vaccine efficacy><vaccine for novel coronavirus><vaccine immune response><vaccine immunogenicity><vaccine induced antibodies><vaccine induced immune response><vaccine study><vaccine trial><vaccine-induced antibodies><vaccines against malaria><vaccines preventing COVID><vaccines to prevent COVID>