Optimal vaccine trial design when estimating vaccine efficacy for susceptibility and infectiousness from multiple populations.

Vaccination can have important indirect effects on the spread of an infectious agent by reducing the level of infectiousness of vaccinees who become infected. To estimate the effect of vaccination on infectiousness, one typically requires data on the contacts between susceptible and infected vaccinated and unvaccinated people. As an alternative, we propose a trial design that involves multiple independent and interchangeable populations. By varying the fraction of susceptible people vaccinated across populations, we obtain an estimate of the reduction infectiousness that depends only on incidence data from the vaccine and control groups of the multiple populations. One can also obtain from these data an estimate of the reduction of susceptibility to infection. We propose a vaccination strategy that is a trade-off between optimal estimation of vaccine efficacy for susceptibility and of vaccine efficacy for infectiousness. We show that the optimal choice depends on the anticipated efficacy of the vaccine as well as the basic reproduction number of the underlying infectious disease process. Smaller vaccination fractions appear desirable when vaccine efficacy is likely high and the basic reproduction number is not large. This strategy avoids the potential for too few infections to occur to estimate vaccine efficacy parameters reliably.

Assessing the effect of HIV vaccination on infectiousness.

Traditionally, measures of vaccine efficacy have focused on a vaccine's ability to prevent infection or disease. HIV vaccination, however, may have important indirect effects by reducing the level of infectiousness of vaccinees who become infected. This latter effect is not captured by the usual estimators of vaccine efficacy. To obtain an estimate of a vaccine's effect on infectiousness, Koopman and Little have proposed a trial design in which HIV-uninfected couples are randomized to the vaccine or control arm of the study. At least one member is assumed to be at risk of HIV infection from outside the partnership. Using this design, we formulate martingales from counting processes which record the number of infected participants over the course of the trial. An alternative estimator of a vaccine's effect on infectiousness along with an estimate of its variance is derived from these martingales. The precision of the estimate is shown to depend on the secondary attack rate within the couple. High secondary attack rates are required for narrow confidence intervals unless very large studies are contemplated.

Statistical issues in the design of HIV vaccine trials.

HIV vaccine trials present significant challenges related to trial endpoints, vaccine efficacy measurement, and the role of nonvaccine interventions. Infection is a valid endpoint for detecting sterilizing immunity. But if the vaccine prevents AIDS without preventing infection, infection may be a misleading surrogate. Appropriate endpoints must be defined for other mechanisms of vaccine action. Direct, indirect, behavioral, and biological effects all determine vaccine efficacy. False security among HIV-vaccine recipients may make negative behavioral effects an important component of vaccine performance. Both biological potency and a more comprehensive program effectiveness should be measured. These goals may require unblinded designs or community randomization. Nonvaccine interventions are currently the only HIV-prevention strategy. Support for larger scale implementation requires more rigorous evaluation that is less dependent on self-reported behavioral changes. The vaccine trial cohorts provide a unique opportunity to cost-effectively evaluate behavioral interventions.

Some statistical issues in HIV vaccine trials.

Efficacy trials of prophylactic HIV vaccines will be among the most difficult clinical trials ever attempted. Not only will there be challenges with the recruitment and retention of high-risk uninfected individuals, there will be many statistical challenges to the design, conduct, analysis, and interpretation of these trials. General features of an efficacy trial are described, including choice for the primary endpoint and testing for and estimating vaccine efficacy. Secondary objectives of trials are also discussed. These include determining the correlates of protective immunity, assessing the impact of HIV genetic variation on vaccine efficacy, and using biological markers such as viral load and CD4+ lymphocyte cell count to gain insight on a vaccine's ability to prevent or delay disease. The use of biological markers as surrogates for disease outcome is discussed. Last, trial designs for studying several candidate vaccines or other HIV prevention strategies in a single trial are examined.

HIV vaccine trials: some design issues including sample size calculation.

Anticipating the availability of one or more candidate HIV vaccines for efficacy testing in the next few years, public health agencies are now planning for the conduct of large-scale efficacy trials. We expect these trials to be randomized, double-blind, placebo-controlled studies with prevention of infection as the primary goal. We discuss in detail factors that influence sample size. Factors most influential are the incidence rate of HIV infection in the study population and the minimum efficacy at which a vaccine is still considered acceptable. The smaller either of these factors is, the larger the sample size will be. The desire to complete trials quickly, the gradual accrual of benefit from vaccination, the inaccuracies of assays to detect infection, the need to counsel participants to avoid exposure to HIV, and loss to follow-up all tend to drive up sample size. To illustrate, 83 subjects per study arm suffice to detect 90% efficacy in a population with a 7% annual risk of infection. This assumes a 3-year study with accrual completed in 1 year, no loss to follow-up, and Types I and II error rates of 5 and 10%, respectively. In contrast, 4,254 subjects per arm are required to identify a 60% effective vaccine in a population with a 1% annual risk. The study is also shortened to 2 years, assumes a 5% annual loss to follow-up, and supposes that the full benefit of vaccination is achieved in 6 months. The most realistic assumptions indicate that trials are very likely to require several thousand participants. Limitations of the proposed designs are also discussed.

Continuous noninvasive monitoring of cardiac output with esophageal Doppler ultrasound during cardiac surgery.

Esophageal Doppler ultrasonography offers a continuous and noninvasive alternative to standard thermodilution cardiac output monitoring. A total of 372 simultaneous measurements of Doppler and thermodilution cardiac output were compared in 16 patients undergoing cardiac surgery. In addition, echocardiographic aortic diameter measurement, necessary for Doppler calibration, was compared with direct surgical measurement in 23 patients. Echocardiographic aortic measurement was often time consuming and correlated poorly (r = 0.31) with surgical measurement. On the other hand, Doppler cardiac output was determined easily and accurately tracked thermodilution cardiac output (R2 = 0.95, common slope coefficient 1.050, by multiple linear regression). Furthermore, Doppler cardiac output was more reproducible, showing less short-term variability than thermodilution cardiac output. The esophageal Doppler technique allows cardiac output monitoring in patients for whom invasive monitoring is not warranted.