The Rotavirus Vaccine Story: A Clinical Investigator's View

Withdrawal of the tetravalent rhesus-human reassortant rotavirus vaccine from our arsenal of vaccines to prevent childhood diseases was a major disappointment. However, the experience demonstrated that the mechanisms established to monitor vaccine safety in the United States functioned effectively. This article reviews how the association with intussusception was discovered and evaluated, and speculates about lessons learned and how to use them.Prelicensure clinical evaluation of the rhesus-human reassortant vaccine was a process that lasted >15 years, cost hundreds of millions of dollars, involved multiple governmental agencies, industry, and dozens of clinical investigators. It was given to >10 000 infants in 27 clinical trials conducted in 9 different countries. After this large and lengthy experience the vaccine was submitted to the Food and Drug Administration (FDA) for consideration for licensure. Concurrently, a Rotavirus Working Group of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) was established to review the safety, immunogenicity, and efficacy of the vaccine to propose recommendations for its use. This working group was composed of experts in pediatric infectious disease, vaccinology, epidemiology, and public health. As part of the review process, a member of the ACIP Working Group reviewed all serious adverse events reported in all of the industry-sponsored trials of all of the rhesus rotavirus vaccine candidates and noted 5 cases of intussusception among 10 054 vaccinees, 3 of which occurred during the week postvaccination, and 1 case among 4633 placebo recipients. None of these cases had been judged by the clinical study investigators to be attributable to the vaccine. The vaccinees with intussusception had participated in 5 different trials and had received 3 different rhesus rotavirus vaccine preparations (rhesus-human reassortant serotype 1 vaccine, tablet preparation of the tetravalent rhesus-human reassortant vaccine, and the subsequently licensed lyophilized tetravalent rhesus-human reassortant vaccine, Rotashield, Wyeth-Lederle Vaccines, Radnor, PA).The ACIP Working Group members concluded that the association of intussusception with the rhesus rotavirus vaccines was more likely to be temporal rather than casual, based on the following observations: 1) infection with human rotavirus strains do not appear to cause intussusception because the occurrence of intussusception is not seasonal, in contrast to the marked seasonality of rotavirus infections; 2) vaccinees developed intussusception at precisely the peak age at which intussusception occurs in the general population; 3) no cases of intussusception occurred after the first dose of the vaccine, when vaccine virus replication is at its peak; and 4) there was no statistical difference between the overall occurrence of intussusception in vaccinees compared with placebo recipients or to the background rate in populations of children <6 months old and <12 months old.Details of these prelicensure intussusception cases were shared with the CDC, FDA, the National Institutes of Health, and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP). The final judgment made was that the data did not justify withholding licensure and use of a vaccine that could prevent 55 000 hospitalizations and approximately 25 deaths annually in this country. However, the FDA included the occurrence of these cases in the package insert and created a search code for intussusception to facilitate tracking of cases reported after vaccine licensure. Additionally, the ACIP and AAP included the intussusception cases in their recommendations to alert physicians to report cases after vaccination.Ten months postlicensure, after administration of approximately 1.5 million doses of vaccine, 15 cases of intussusception had been reported to the Vaccine Adverse Events Reporting System (VAERS), a passive surveillance system established to detect vaccine side effects. Thirteen of these children developed intussusception after the first dose of rotavirus vaccine at a median age 3 months, which is younger than the median age of intussusception in the background population. Preliminary analysis of a postlicensure study at Northern Kaiser Permanente and of a case control study in Minnesota also suggested an increased risk of intussusception shortly after receipt of Rotashield. These data were sufficiently concerning that the CDC and the AAP immediately issued an alert to suspend vaccination while the CDC conducted an urgent case-control study. As a result of the CDC investigation, it became clear that there was a markedly increased risk of intussusception shortly after dose one of Rotashield and that a smaller increase in risk occurred after dose two. No association was demonstrated after dose three. Most cases occurred between day 3 and day 7 postvaccination, but a slightly increased association existed through the second week postvaccination.After review of these data, the manufacturer voluntarily withdrew the vaccine from the market. This decision was made quickly and was appropriate for the United States based on the data at hand. The ACIP and AAP subsequently withdrew recommendations for use of the vaccine in the United States. Use of this vaccine still may be indicated in areas of the world were the mortality rates from rotavirus infection outweigh the risk of vaccine-associated intussusception.This experience has stimulated intense scrutiny of the process whereby vaccines are licensed, recommended for use, and monitored for safety in this country. Retrospective use of the newly developed person-time analysis of events indicates 3 prelicensure cases of intussusception occurring the week after vaccination was more cases than would have been anticipated. However, only 1 of these prelicensure cases fit the profile of vaccine-associated cases, and that child had not received Rotashield. The other 4 prelicensure cases occurred either after dose three or >2 weeks after vaccination. Consequently, even with the benefit of hindsight, it does not appear that the prelicensure experience predicted that a causal association existed.This posthoc evaluation indicates that our vaccine development, evaluation, and postlicensure surveillance system was sufficiently thorough and effective because all involved worked in an open, responsible, and cooperative fashion. A possible side effect was detected, evaluated, publicized and noted in the package insert and recommendations, specifically looked for postlicensure, and immediately acted on when VAERS detected a signal.Should there be changes in how future vaccine candidates are evaluated? It has been proposed that a data safety monitoring board with a statistician experienced in assessment of rare events should be established for all studies of new classes of vaccines. That is a good suggestion, but it would not have detected the association of intussusception with rotavirus vaccine because no more than 1 case occurred in any one trial. Thus the feasibility of establishing a database of serious adverse events occurring in all trials of similar products should be explored. Confidentiality issues may make this approach problematic, but it would be a means to enlarge sample sizes for detection of rare adverse events.Evaluation of 10 000 infants was not a sufficient safety experience to have demonstrated an association of rotavirus vaccine and intussusception because the excess risk of intussusception was approximately 1 per 5000 vaccinated children. How many children are required to satisfy us that a vaccine is safe to license and recommend? This is somewhat of a “catch-22” question because to accurately perform that calculation you must already know what side effect you are looking for and the rate at which it occurs in vaccinees versus controls. One can determine how many children must be studied to determine various numbers of serious adverse events. This still leaves very difficult risk-benefit decisions, such as how many serious adverse events are acceptable to save a life.One approach is to simply require an arbitrarily large safety experience prelicensure. That may provide some comfort, but there are difficulties with it. Informed consent must be obtained if such a study is performed prelicensure, rendering the study enormously expensive and possibly driving the cost of vaccine to the point of being unaffordable for universal use. Requiring huge sample sizes also would delay the availability of vaccines that could be preventing deaths. An option is for the ACIP, AAP, and American Academy of Family Physicians to issue suggestions for use rather than frank recommendations that have medico-legal implications for practitioners. However, this shifts responsibility to busy primary care physicians and parents who may not have access to sufficient data to make an informed choice.There currently is a difficult economic reality for the recommending bodies, which is that the vaccine is unlikely to be covered by insurance if it is not recommended for use. Consequently, the vaccine would not be available to economically disadvantaged children. This creates strong pressure to recommend the use of vaccines in situations where the decision may be more appropriately made by physicians and parents. Perhaps this obstacle might be circumvented by coverage of licensed vaccines for specified indications by the Vaccines for Children Program and enactment of laws to require similar coverage by private insurers, regardless of whether the vaccine is officially “recommended.”The reality is that prelicensure experience with vaccines cannot be large enough to detect all very rare adverse events. It is neither logistically nor economically feasible. Only after extensive postlicensure experience with a vaccine can the entire safety and effectiveness profile emerge. Sometimes very positive postlicensure discoveries occur. For example, it was after licensure and widespread use of the conjugate Haemophilus influenzae type b vaccines that herd immunity was appreciated. A rational approach is to focus efforts on improving postlicensure reporting of possible vaccine adverse effects and vaccine failures to ensure rapid detection of problems. That is what was done with the rotavirus vaccine and it worked. Our current vaccine safety surveillance systems are good and will be even more effective if all practitioners make themselves aware of possible vaccine adverse events by carefully reading vaccine package inserts and recommendations and by reporting all serious adverse events temporally related to a vaccine dose to VAERS (800-822-7967;www.fda.gov/cber/vaers/report.htm).Unforeseen, unfortunate events have occurred throughout the history of vaccinology and will continue to occur as we strive to bring new products to protect our children against disease. No medical intervention, including immunizations, is without some risk and no amount of effort will make vaccines completely risk-free. However the enormous benefits of vaccination far outweigh the small risks of serious side effects. The public, practitioners, investigators, manufacturers, and governmental agencies must continue to cooperate to learn continually from these events to advance the field.Sincere appreciation is expressed to Drs James Campbell, Kathryn Edwards, Susan Ellenberg, Roger Glass, Neal Halsey, Carole Heilman, Albert Kapikian, Samuel Katz, Karen Kotloff, Myron Levine, John Livengood, John Modlin, Trudy Murphy, Peter Paradiso, Regina Rabinovich, Melinda Wharton, and Kathryn Zoon for their helpful suggestions and support. I express very special thanks for Dr Marshall Rennels' support throughout.