Making vaccination policy: the experience with rubella.

The massive rubella epidemic of 1962-1965 stimulated the development of rubella vaccine. Once vaccines were developed, the U.S. vaccination program, initially focused on infants and children, reduced both rubella and congenital rubella. However, later extension of vaccination to certain older age groups achieved significantly better control. While rubella clearly is not the perfect model for pertussis, a review of its history is illuminating. Current rubella vaccination policies resulted from an evolution in scientific understanding. Controversies, including those related to communicability, reactivity, and teratogenicity of the rubella vaccine virus, duration of immunity following vaccination, and protection following reinfection, led countries to use different approaches for national immunization programs. These differences were eventually resolved by clinical and epidemiological research coupled with rigorous scientific debate. Increased scientific understanding of pertussis, its epidemiology, and the effects of the new pertussis vaccines will similarly enable informed decision making on whether to extend pertussis immunization to adolescents and adults.

Safety of biopharmaceuticals: a current perspective.

The impetus for this conference comes in large measure from the continuing development of the ICH Viral Safety document concerned with testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin [1]. My opening remarks for this conference were, I think, suggested by the organizers in the belief that George Santayana's quote, "Those who cannot remember the past are condemned to repeat it" has validity for this effort. In this brief review I have tried to recall some past unfortunate episodes and outline the lessons that they might have for us. I have also attempted to outline a number of issues which I believe are critical to the success of efforts to guarantee, as much as humanly possible, the safety that we seek balanced against our ability to develop and use important new products.

Viral vaccines and antivirals: current use and future prospects.

The evolution of viral vaccines from the time of Jennerian prophylaxis to today's recombinant technology has been a continuing story of success. From the relatively crude or "first generation" vaccines for smallpox, rabies, and yellow fever followed a second and third generation of improved or new viral vaccines. The application of techniques for attenuating, inactivating, and partially purifying candidate viruses yielded safe, effective vaccines against influenza, poliomyelitis, measles, mumps, and rubella. With the advent of effective national immunization programs in the United States and other areas of the world to promote wide scale use of these vaccines, we have seen a dramatic decrease in incidence of the viral infections of childhood. The new biotechnology serves as the cornerstone for a fourth generation of vaccines and has already provided a licensed recombinant yeast human hepatitis B vaccine. The prospects for a wide spectrum of new or improved vaccines are highly encouraging, not only because of the recent technical advances but also because vaccine development has been recognized as a priority area of research. Under the National Institute of Allergy and Infectious Diseases' Program for Accelerated Development of New Vaccines, support is being provided for developmental vaccine studies with hepatitis A and B, influenza A and B, rabies, rotavirus, varicella, and respiratory syncytial virus (53). The outlook for antivirals is equally optimistic. The same technologies that have provided greater insight into the genetics and molecular biology of viruses and hence the means to fashion subunit or even synthetic vaccines have yielded data that can be applied to successful development of targeted antiviral compounds.

Bioequivalence of generic thioridazine drug products--the FDA viewpoint.

The phenothiazines are among the most widely used drugs to treat symptoms commonly associated with acute and chronic psychoses. One of the commonly prescribed compounds within this class of drugs is thioridazine, available both as a generic product as well as the innovator product, Mellaril. Each of these products is coded as bioequivalent and consequently therapeutically equivalent by the Food and Drug Administration (FDA). A recent issue of this journal contained an article that raised a number of questions concerning the bioequivalence of the generic versions of thioridazine that have been approved by the FDA. Their article was based in part on information obtained from the FDA as well as information supplied to the authors by Sandoz, Inc., the manufacturer of the original thioridazine drug product Mellaril. The FDA has reviewed its original decision of bioequivalence. Based on this reassessment, the FDA strongly rejects the assertion by the authors that several of the approved generic thioridazine products are not bioequivalent. The rationale behind the FDA decisions and the FDA's viewpoint on the bioequivalence of generic thioridazine drug products is discussed in detail.

Control of measles and rubella through use of attenuated vaccines.

A summary report of the current status of morbidity and mortality associated with measles and rubella vis á vis immunization practices in the United States since these vaccines were licensed in 1963 (measles) and 1969 (rubella) is presented.

Review of existing vaccines for influenza.

The problems of producing and distributing influenza vaccines are described as well as effectiveness and adverse reactions. It appears that Guillain-Barré (GBS) is likely to be encountered with the use of any of the inactivated influenza vaccines.

Summary of clinical trials of influenza virus vaccines in adults.

Trials in approximately 3,900 adults were conducted with influenza A/New Jersey/76, A/Victoria/75, and B/Hong Kong/72 virus vaccines. Subjects were observed following a standard protocol, and serologic testing was performed in a single laboratory. The data indicate that prior experience of the population with earlier influenza viruses ("priming") is a determinant in response to vaccination. Thus, participants older than 25 years showed good serologic response following a single inoculation of A/New Jersey/76 virus, while younger persons responded poorly. Serological responses to A/Victoria/75 and B/Hong Kong/72 viruses were, in contrast, equally good in the younger and older adults. Whole-virus vaccines were measurably more reactive than split-virus vaccines, a finding more easily discernined in unprimed populations. In the unprimed persons, a single dose of split-virus vaccine was less immunogenic than a single dose of whole-virus vaccine. The presence of preexisting antibodies appeared to reduce systemic reactivity. For adequate immunization of a totally unprimed population, a single relatively large and reactive dose of whole-virus vaccine or two, properly spaced, smaller nonreactive doses of either whole-virus vaccine or split-virus vaccine would be required.

Antibody persistence after primary immunization with trivalent oral poliovirus vaccine.

Five years after primary infant immunization with trivalent oral poliovirus vaccine, employing either a three-dose primary series as recommended by the U.S. Public Health Service Advisory Committee on Immunization Practices (ACIP) or a four-dose series as recommended by the Committee on Infectious Diseases of the American Academy of Pediatrics. 115 children were serologically tested for persistence of neutralizing antibodies by the microneutralization test. Of the 57 individuals immunized according to the ACIP recommendation, antibody persistence was demonstrated in 92% for type 1 poliovirus, 98% for type 2, and 84% for type 3. Of those 58 individuals originally receiving a four-dose primary infant immunization series, the persistence of antibody was 98% to type 1, 98% to type 2, and 87% to type 3. Twenty-one of 24 negative sera showed neutralizing ability when tested by a more sensitive plaque reduction test. Thus, individuals completing either immunization schedule demonstrated satisfactory persistence of neutralizing antibody to all three poliovirus types over a five-year period.

Isolation of foamy virus from rhesus, African green and cynomolgus monkey Leukocytes.

Foamy virus (FV) was recovered regularly from the leukocyte of rhesus and cynomolgus monkeys and somewhat less often from African green monkey leukocytes. Virus was found in virtually all organs of experimentally infected rhesus monkeys. No illness or pathologic abnormalities were noted in these animals or in any of the naturally infected animals in spite of the prolonged period of viral persistence in various organs and tissues.

Automated microtransfer technique for the assay of poliovirus- and mumps virus-neutralizing antibodies.

Use of an automated apparatus to quantitate mumps virus- and poliovirus-neutralizing antibody is described. The automated titration equipment affords savings in effort, time, and reagents in conducting large-scale surveys for the determination of mumps- and poliovirus-neutralizing antibodies. This technique has been found to be reproducible and gives results comparable to other antibody assay methods.