Updates: Smallpox vaccine trial; D4T phenotypic resistance; VAQTA withdrawal
January 1, 2002 3 minutes read
Smallpox Vaccine Trials Begin
Source: ProMED-mail post, Nov. 17, 2001. www.promedmail.org.
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You never thought you’d see the day. The NIAID has initiated a large-scale trial of smallpox vaccination of 684 adults at 4 clinical research sites throughout the United States. About 15 million doses of the Dryvax smallpox vaccine (Wyeth Laboratories) were stockpiled about 20 years ago. In an attempt to preserve as much vaccine for as many patients as possible, the NIH is hoping to determine whether serial dilutions of vaccine may be as effective as the original formulation. Patients are being randomized to receive full-strength vaccine, or dilutions of 1:5 or 1:10. Because the production of a scab at the site of vaccination is believed to correlate well with protective immunity, patients who do not develop one within 7-9 days of vaccination, or who fail to develop antibodies, will receive a booster dose of the same formulation as their initial dose. A testament to the times, the study has rapidly accrued.
D4T Phenotypic Resistance
Source: Ross L, et al. AIDS Res Hum Antiretrovir. 2001;17:1107-1115.
Studies suggest that the ad-ministration of stavudine (D4T), independent of zidovudine (AZT), may induce HIV genotypic mutations commonly associated with AZT resistance (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/F). Such thymidine analogue mutations—or TAMs—may result in decreased susceptibility to D4T at much lower levels than previously suspected.
Ross and colleagues examined HIV-1 isolates from patients virologically failing D4T-containing regimens, all of whom were AZT naïve. TAMs were present in 28%, and 35% of the isolates contained either TAMs or the Q151M multinucleoside resistance (MNR) mutation. HIV isolates obtained from patients with TAMs or MNR mutations showed significantly decreased phenotypic susceptibility to D4T, with an average 3-fold increase in IC50 to d4T using the PhenoSenseTM HIV Assay (ViroLogic Inc., South San Francisco, Calif). For this reason, we have recently adopted a fold change of > 1.6 as the break-point for D4T resistance.
VAQTA Withdrawal Creates a Stir
Source: ProMED-mail post, Dec. 5-14, 2001, www.promedmail.org; Eurosurveillance Weekly, Dec. 5, 2001; [email protected].
Merck and Aventis Pasteur (which markets this Merck product in the EU) recently announced the "recall" of VAQTA hepatitis A vaccine in the United States and European Union (EU). The recall affects a wide number of lots of vaccine, as well as possibly some generic vaccine, including all vaccine in prefilled syringes within the EU within its current expiration date, as well as pediatric and adult vaccine dating back to 1997-1998 (possibly more than 500,000 doses of vaccine!). The problem in the United States is less widespread and affects ~170,000 doses. The basis for the withdrawal was an inadequate antigen content in some prefilled syringes, which may fail to induce protective immunity.
While the appropriate antibody level needed to provide protection from hepatitis A disease is not known, and reports of vaccine failure are rare, the companies are recommending that all affected patients be identified and receive revaccination with an alternate product or have their antibodies checked. Public health authorities in different countries are providing varied recommendations, but many suggest that patients should be notified and that 1) patients who received a single dose for travel should be immediately contacted before departure, if possible, and revaccinated; and 2) patients who have completed the vaccine series should receive an entirely new series with an alternate vaccine.
Under the gun, and fearful of the medical legal consequences (especially in the United States), physicians and travel clinics are laboring to identify affected patients—an onerous task when individual vaccine records are maintained or lot numbers are not readily available. Rescreening and revaccinating hundreds of subjects, especially when insurance companies may not cover the costs, may be overwhelming to private practices and travel clinics with already thin margins. Merck has offered to provide free serologic testing through a central location (to be determined) for those who received vaccine from an affected lot, as well as free vaccine for those with inadequate titers, but even this creates logistical problems for physicians and clients.
Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor of Infectious Disease Alert.
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