# VAccine failure: natural history and determinants of post-vaccination Covid-19

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2024 · —

## Abstract

As SARS-CoV-2 vaccines enter mass distribution, little is known about vaccinated individuals who nonetheless
develop Covid-19 (symptomatic disease or “vaccine failure”), require hospitalization, and die. Pfizer-BioNTech
reported 3.8 vaccine failure cases/1,000 person-years, meaning vaccine failure will be relatively common on a
population level. Pfizer, Moderna, and Janssen vaccine efficacy trials involved 35,000 to 50,000 individuals
from which there are insufficient numbers to study vaccine failure, calling for post-vaccination surveillance with
observational cohort studies in real-world settings. Using the VHA Corporate Data Warehouse (CDW) and the
Covid-19 Shared Data Resource, we can harness real-time data to design a forward-thinking, active
surveillance system to pragmatically study the epidemiology of vaccine failure. Our overarching goals in the
proposed VAccine Failure study are to characterize post-vaccination Covid-19 clinical outcomes and
identify factors associated with vaccine failure. Our central hypothesis is that adverse Covid-19 clinical
outcomes after vaccination will be increasingly common over time, driven by delayed vaccination, clinical
factors associated with weak or rapidly declining immune responses, and viral lineages accumulating escape
mutations. We propose to identify a national longitudinal cohort of all Veterans age >65 years who had a
primary care visit in the VA within the past 2 years and received at least 1 dose of any SARS-CoV-2 vaccine
(N>1.55 million Veterans). We will observe these Veterans for up to 3.5 years and ascertain diagnoses of
Covid-19 incidence or vaccine failure (acute SARS-CoV-2 infection + at least 1 symptom), hospitalization, and
mortality. We will leverage our extensive experience conducting observational cohort studies with VA and
Medicare data to emulate a target trial approach and achieve the following Aims, rooted in the epidemiological
triad: Aim 1. To describe and compare Covid-19 clinical outcomes by vaccine type and manufacturer in a
population-based national cohort of SARS-CoV-2 vaccinated Veterans. Aim 2. To determine environmental
factors associated with vaccine failure. Aim 3. To determine host factors associated with vaccine failure. Aim
4. To determine agent factors associated with vaccine failure. To achieve Aim 4, we will use a case-control
study of 600 Veterans with Covid-19 to identify cases with the outcome of viral variant and perform density
sampling of controls from our SFVAHCS/VISN-21 catchment area, where we have access to banked remnant
SARS-CoV-2 PCR-positive samples. This project is uniquely positioned to provide the National VA Vaccine
Program with real-time evidence to rapidly adapt its vaccine delivery for Veterans (e.g., vaccine boosters for at-
risk groups; timing of next-generation vaccines) while filling the urgent national need for post-vaccination
surveillance in real-world settings.

## Key facts

- **NIH application ID:** 10909822
- **Project number:** 5I01CX002417-03
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** John Daniel Kelly
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909822

## Citation

> US National Institutes of Health, RePORTER application 10909822, VAccine failure: natural history and determinants of post-vaccination Covid-19 (5I01CX002417-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909822. Licensed CC0.

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