Leaky Vaccines Protect Highly Exposed Recipients at a Lower Rate: Implications for Vaccine Efficacy Estimation and Sieve Analysis

“Leaky” vaccines are those for which vaccine-induced protection reduces infection rates on a per-exposure basis, as opposed to “all-or-none” vaccines, which reduce infection rates to zero for some fraction of subjects, independent of the number of exposures. Leaky vaccines therefore protect subjects with fewer exposures at a higher effective rate than subjects with more exposures. This simple observation has serious implications for analysis methodologies that rely on the assumption that the vaccine effect is homogeneous across subjects. We argue and show through examples that this heterogeneous vaccine effect leads to a violation of the proportional hazards assumption, to incomparability of infected cases across treatment groups, and to nonindependence of the distributions of the competing failure processes in a competing risks setting. We discuss implications for vaccine efficacy estimation, correlates of protection analysis, and mark-specific efficacy analysis (also known as sieve analysis).

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Vaccine Efficacy at a Point in Time

10.1101/2021.02.04.21251133 ◽

2021 ◽

Author(s):

Dean Follmann ◽

Michael Fay

Keyword(s):

Vaccine Efficacy ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Vaccine Trial ◽

Phase Iii ◽

Cross Sectional ◽

Transmission Potential ◽

Viral Loads ◽

Hazards Model ◽

Vaccine Effect

AbstractVaccine trials are generally designed to assess efficacy on clinical disease. The vaccine effect on infection, while important both as a proxy for transmission and to describe a vaccine’s total effects, requires frequent longitudinal sampling to capture all infections. Such sampling may not always be feasible. A logistically easy approach is to collect a sample to test for infection at a regularly scheduled visit. Such point or cross-sectional sampling does not permit estimation of classic vaccine effiacy on infection, as long duration infections are sampled with higher probability. Building on work by Rinta-Kokko and others (2009) we evaluate proxies of the vaccine effect on transmission at a point in time; the vaccine efficacy on prevalent infection and on prevalent viral load, VEPI and VEPV L, respectively. Longer infections with higher viral loads should have more transmission potential and prevalent vaccine efficacy naturally captures this aspect. We apply a proportional hazards model for infection risk and show how these metrics can be estimated using longitudinal or cross-sectional sampling. We also introduce regression models for designs with multiple cross-sectional sampling. The methods are evaluated by simulation and a phase III vaccine trial with PCR cross-sectional sampling for subclinical infection is analyzed.

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Reporting of Multivariable Methods in the Medical Literature

Journal of Investigative Medicine ◽

10.2310/jim.0b013e31818914ff ◽

2008 ◽

Vol 56 (7) ◽

pp. 954-957 ◽

Cited By ~ 12

Author(s):

Jeanette M. Tetrault ◽

Maor Sauler ◽

Carolyn K. Wells ◽

John Concato

Keyword(s):

Logistic Regression ◽

New England ◽

Proportional Hazards ◽

Medical Literature ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Primary Method ◽

Primary Analysis ◽

Proportional Hazards Assumption ◽

Complete Reporting

BackgroundMultivariable models are frequently used in the medical literature, but many clinicians have limited training in these analytic methods. Our objective was to assess the prevalence of multivariable methods in medical literature, quantify reporting of methodological criteria applicable to most methods, and determine if assumptions specific to logistic regression or proportional hazards analysis were evaluated.MethodsWe examined all original articles in Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, and New England Journal of Medicine, from January through June 2006. Articles reporting multivariable methods underwent a comprehensive review; reporting of methodological criteria was based on each article's primary analysis.ResultsAmong 452 articles, 272 (60%) used multivariable analysis; logistic regression (89 [33%] of 272) and proportional hazards (76 [28%] of 272) were most prominent. Reporting of methodological criteria, when applicable, ranged from 5% (12/265) for assessing influential observations to 84% (222/265) for description of variable coding. Discussion of interpreting odds ratios occurred in 13% (12/89) of articles reporting logistic regression as the primary method and discussion of the proportional hazards assumption occurred in 21% (16/76) of articles using Cox proportional hazards as the primary method.ConclusionsMore complete reporting of multivariable analysis in the medical literature can improve understanding, interpretation, and perhaps application of these methods.

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Molecular genotyping and phenotyping of Vibrio vulnificus isolated from diseased, brown-marbled grouper (Epinephelus fuscoguttatus) in Thailand with preliminary vaccine efficacy analysis

Aquaculture ◽

10.1016/j.aquaculture.2021.737188 ◽

2021 ◽

pp. 737188

Author(s):

Atittaya Hoihuan ◽

Patcharee Soonson ◽

Paiboon Bunlipatanon ◽

Jumroensri Thawonsuwan ◽

Varin Tanasomwang ◽

...

Keyword(s):

Vaccine Efficacy ◽

Vibrio Vulnificus ◽

Molecular Genotyping ◽

Efficacy Analysis ◽

Epinephelus Fuscoguttatus

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Immune Responses and Protection against Experimental Brucella suis Biovar 1 Challenge in Nonvaccinated or B. abortus Strain RB51-Vaccinated Cattle

Clinical and Vaccine Immunology ◽

10.1128/cvi.00326-10 ◽

2010 ◽

Vol 17 (12) ◽

pp. 1891-1895 ◽

Cited By ~ 11

Author(s):

S. C. Olsen ◽

S. G. Hennager

Keyword(s):

Immune Responses ◽

Experimental Infection ◽

Brucella Abortus ◽

Agglutination Test ◽

Saline Control ◽

Infected Cattle ◽

Infection Rates ◽

Treatment Groups ◽

Brucella Suis ◽

Fluorescence Polarization Assay

ABSTRACT Twenty Hereford heifers approximately 9 months of age were vaccinated with saline (control) or 2 × 1010 CFU of the Brucella abortus strain RB51 (RB51) vaccine. Immunologic responses after inoculation demonstrated significantly greater (P < 0.05) antibody and proliferative responses to RB51 antigens in cattle vaccinated with RB51 than in the controls. Pregnant cattle received a conjunctival challenge at approximately 6 months of gestation with 107 CFU of B. suis bv. 1 strains isolated from naturally infected cattle. The fluorescence polarization assay and the buffered acid plate agglutination test had the highest sensitivities in detecting B. suis-infected cattle between 2 and 12 weeks after experimental infection. Serologic responses and lymphocyte proliferative responses to B. suis antigens did not differ between control and RB51 vaccinees after experimental infection. No abortions occurred in cattle in either treatment group after challenge, although there appeared to be an increased incidence of retained placenta after parturition in both the control and the RB51 vaccination treatment groups. Our data suggest that the mammary gland is a preferred site for B. suis localization in cattle. Vaccination with RB51 did not reduce B. suis infection rates in maternal or fetal tissues. In conclusion, although B. suis is unlikely to cause abortions and fetal losses in cattle, our data suggest that RB51 vaccination will not protect cattle against B. suis infection after exposure.

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