Considerations of Candidate Vaccines
The committee was charged with considering up to 30 candidate vaccines using analytic model that it developed. Far more than 30 candidate vaccines are in the research and development (R&D) pipeline. The committee struggled early in its deliberations to select the candidate vaccines to be analyzed for this report. The committee followed a modified delphi approach and winnowed a very long list of candidates into a manageable and meaningful list of 26 candidate vaccines (see Table 3–1). The committee was guided in their final decisions by its charge to consider vaccines directed against conditions of domestic health importance that could be licensed within 20 years. The committee was further guided by a set of rather firm exclusion criteria, additional considerations of a qualitative nature regarding the benefits of certain vaccines and avenues of R&D, and finally, by considerations of vaccine program implementation and utilization. Each of these points will be discussed in turn.
The committee was guided in their choices by a set of exclusion criteria. The following were bases for exclusion: (1) conditions for which basic science information was insufficient to predict vaccine development and licensure within 20 years; (2) potentially vaccine-preventable conditions for which other preventive interventions were deemed more appropriate; and (3) diseases of primarily non-domestic health importance. These exclusion criteria were used in the analysis undertaken for this report in order to establish a more manageable task for the committee. The exclusion criteria were not intended to guide public policy on vaccine R&D investments by either the public or private sector.
TABLE 3–1 Candidate Vaccines Included for Full Analysis*
Insufficient Basic Science Information
The Committee judged that a vaccine approach to control a number of diseases caused by microorganisms was not attainable within the next 20 years. In some instances not enough information was available concerning the antigens that stimulate protective immune response or the host responses necessary to provide protection. In other cases, a class of infectious agents are known to cause disease (e.g., periodontal disease), but the major contributors to disease within that class are not yet identified. In other cases, knowledge of the natural history of the infection was inadequate. Some of these infectious diseases against which vaccines were not yet considered feasible occur in healthy hosts who experience the loss of integrity of the skin or the disruption of normal intestinal barriers to microorganisms, which permits the development of secondary infections (e.g., infections caused by Clostridium perfringens or Bacteroides fragilis). Other diseases are the result of intimate exposure of healthy hosts to others who harbor certain pathogens (e.g., Treponema pallidum and Mycobacte
riun leprae). Still others occur in individuals with underlying medical conditions that impair host defenses, allowing an opportunistic agent to become invasive (e.g., enterococci) or the acquisition of nosocomial agents (e.g., Serratia marcescens). Innovative or expanded methods for preventing nosocomial infections, with their multitude of potential specific etiologic agents, make immunization an inferior option. This list of pathogenic microorganisms excluded from consideration due to lack of scientific knowledge is not intended to be exhaustive, and the following illustration for one agent is intended to provide a rationale that would be common to several others.
Syphilis is a prominent example of an infection in the immunocompetent host that poses both a substantial disease burden and a substantial expenditure of public health resources in the United States, and against which the development of a vaccine seems unlikely in the near future. The late 1980s saw a dramatic resurgence of syphilis, especially among women (with a parallel increase in congenitally acquired infections) and among ethnic minority groups in urban areas. At least 20,000 cases of primary or secondary syphilis are reported each year, but it is estimated that only one in three or four cases is reported. Because this is a sexually transmitted infection, both the infected individual and the exposed sexual partner require counseling, diagnostic testing, treatment, and follow-up testing.
The causative agent, T. pallidum, has a complex morphology and composition. An outer membrane surrounds the endoflagella, cytoplasmic membrane, and the protoplasmic cylinder. It also is believed that T. pallidum has a glycosaminoglycan surface layer that is antiphagocytic. The organism also has more than 15 major protein constituents, some of which are covalently linked to fatty acids. The outer membrane consists of a lipid bilayer, presumably with few proteins. However, the precise cellular locations of these antigens and the identities of nonprotein constituents remain controversial.
Humoral immunity in syphilis has been studied for nearly a century. Human infection uniformly invokes immunoglobulin G (IgG) and IgM antibodies to a wide variety of T. pallidum proteins, but that infection progresses to secondary and eventually tertiary manifestations unless specific therapy is administered. Passive administration of serum from rabbits recovering from experimental infection attenuates but does not prevent infection. This finding and other evidence suggest that humoral immunity is not sufficient for the prevention of infection, and recent data indicate that cellular immune mechanisms are considerably more important. Thus, most experts conclude that despite the impressive disease burden attributable to syphilis, there is insufficient knowledge concerning mechanisms of protective immunity to T. pallidum to propose that a vaccine be developed in the near future.
Existence of Appropriate Prevention Interventions
For a number of important diseases caused by microorganisms, the committee judged a vaccine approach to be secondary compared to other public health measures for disease prevention and control. Most important among these were the great number of nosocomial infections that occur annually in the United States. These result from contamination or other conditions of hospital care that lend themselves to prevention through improved adherence to infection control procedures and universal precautions.
Prominent offending organisms in this category include Pseudomonas aeruginosa, enterococci, and Staphylococcus aureus. Of these, only P. aeruginosa is responsible for a significant disease burden in other contexts, such as cystic fibrosis, and even in patients with cystic fibrosis, new and innovative approaches to treating/managing the pathophysiology of the underlying disease make specific immunization a secondary option.
Another example of candidate vaccines that the committee chose not to include are waterborne pathogens. Again, this exclusion is not meant to discount the disease burden imposed by such agents but rather to emphasize that wellestablished and validated public health principles are available to meet the challenge of contaminated water supplies.
A third transmission mode that can be better approached by strategies other than direct immunization involves vector-borne microbial agents. In almost all instances in the United States in which vectors are involved in the transmission of serious infectious diseases, vector control is a more appropriate public health option than large-scale immunization efforts.
Finally, a number of infections of increasing importance in the United States occur in immunocompromised hosts. With the continuing HIV epidemic, the size of the susceptible immunocompromised population is increasing, and so the numbers of infections are growing among such individuals. Nevertheless, vaccine strategies are not viewed as a high priority in that setting, if only because the underlying condition that renders the host susceptible makes immunization unlikely to provide protection. That is not to say that anticipatory immunization with some of the established vaccines cannot play an important role in early intervention; rather, the range of infections caused by organisms against which new vaccines would be needed are unpredictable in a given host and occur only when the immune response is already deeply impaired.
International Burden of Disease
Without question, the great unsolved “giant” problems of global infectious disease (see Murray and Lopez, 1996) are very different from the list of priority problems that the committee has developed for the United States. Although malaria was of tremendous importance during the early history of this country, it
currently occurs only sporadically among travelers returning from areas where the disease is endemic and/or rarely in limited local outbreaks secondary to their return. With such infrequent and narrow threats, efforts at vector control have proved adequate U.S. public health responses.
However, malaria is an enormous problem elsewhere, with a high morbidity and mortality burden (3 million deaths per year). The emergence of multiple-drug-resistant variants of Plasmodium, along with insecticide resistance among the vectors of malaria coupled with environmental impediments to vector control, are all factors that make a vaccine approach to malaria control a matter of high priority when assessed from a global perspective. Furthermore, the scientific status of malaria vaccine research promises that exciting progress may be at hand (IOM, 1996b). Therefore, although the mandated U.S. focus of the project does not include malaria, a global overview would surely place it at a high level in a list of priorities—not only malaria but, indeed, all parasitic diseases (e.g., schistosomiasis, leishmaniasis, and Chagas disease) were excluded from the committee’s analysis despite their high global toll on health. Finally, some diseases are of marginal importance to U.S. citizens except during military service.
The committee has included in its analysis candidate vaccines that would be of great international benefit in addition to that gained with domestic use. Its analysis, however, does not include benefits to be gained by such international use. An analysis that included international disease burden might well have significant impact on the results (ranking or grouping into broad categories of benefits) of the modeling. For example, the resurgence of tuberculosis in the United States, and especially the emergence of multiple-drug-resistant strains, is of sufficient concern to raise it to a high level of concern even in U.S. terms. Globally, however, it dwarfs all other pathogens, causing 3 million deaths per year. It is the proximate cause of approximately half of AIDS deaths in Africa. Along with the emergence of HIV in Asia, where tuberculosis is highly prevalent, it is likely to assume even greater dominance as the most lethal infectious pathogen of humans.
Similar changes in priority might be seen for viral and bacterial respiratory infectious diseases. Improved vaccines against RSV, Streptococcus pneumoniae, and group A streptococci, among other agents, would also be included on a global priority ranking. Likewise, enteric viruses such as rotavirus and bacteria such as Shigella are important contributors to mortality worldwide.
ADDITIONAL CONSIDERATIONS FOR INCLUSION
In addition to the explicit inclusion criteria based on the charge to discuss candidate vaccines of domestic health importance and feasibility of licensure, the committee seriously considered candidate vaccines for reasons other than judgment about disease burden and likelihood of development within 20 years.
The committee notes that a policymaker concerned with decisions about investing in vaccine R&D might consider on an ad hoc basis a candidate vaccine that precipitously emerges in importance for any of several reasons (e.g., sudden shift in disease epidemiology, genetic variations, or new information linking an infectious agent to serious and chronic disease). Obviously, the committee could not second-guess such a situation and include an example.
The committee included three candidate vaccines of primary importance to a geographically restricted target population. These candidate vaccines are directed against Coccidioides immitis, Histoplasma capsulatum, and Borrelia burgdorferi. The analysis of these candidate vaccines illustrates how regionally important candidate vaccines stand in a ranking based on national importance. If one assessed the potential benefit of these vaccines compared to other candidate vaccines for those regions alone, the benefits might be quite large and apparent. The committee’s model could also be used for such an assessment of regional vaccine programs.
The committee made an explicit decision to include in its analysis two candidate vaccines that were very far along in the development process. The committee knew that vaccines for both rotavirus and Borrelia burgdorferi could be licensed before the report was completed. In fact, vaccines for these pathogens were licensed in August 1998 and December 1998, respectively. The committee believed that readers of the report might wish to know how these vaccines compare to others in an analysis such as that performed for this report. In addition, it should be noted that the newly licensed vaccine for Borrelia burgdorferi is currently approved by the Food and Drug Administration for use only in people between 15 and 70 years of age. The analysis in the report is for a vaccine licensed for use in infancy. The rotavirus vaccine recently licensed matches the candidate vaccine analyzed in the report.
Other important reasons considered by the committee for including a candidate vaccine were that the population most at risk for the disease is very vulnerable. The committee ultimately decided not to include in its analysis a candidate vaccine against Pseudomonas aeruginosa. This infection is an important source of morbidity and mortality in persons with cystic fibrosis. It was not, however, felt to be a significant source of disease in otherwise healthy individuals. Other examples of vulnerable populations considered by the committee include organ transplant patients and persons otherwise immunocompromised, such as those with AIDS. Such populations are sometimes quite small, but the potential reductions in health care costs and improvements in health status by preventing infections make development of certain candidate vaccines worth considering.
Finally, vaccine development efforts for some diseases that impose relatively little disease burden can lead to scientific advances that will be influential for vaccine R&D years later for candidate vaccines for other diseases. For example, the committee believed that research into a vaccine against Streptococcus mutans will lead to benefits far beyond those achieved by prevention of dental
caries. The basic and applied science of mucosal immunity will influence vaccine research for many candidate vaccines in the future. The committee did not include candidate vaccine for S. mutans in its analysis, but recognizes the incalculable benefit to basic science of current vaccine research in the area.
The inclusion of therapeutic vaccines directed against autoimmune diseases such as rheumatoid arthritis or multiple sclerosis is a departure from a traditional array of candidate vaccines. Because there are no licensed therapeutic vaccines, understanding of when health benefits could be realized in the course of disease with a vaccine strategy is incomplete. The varied pathophysiology of such diseases also leads to varying expectations regarding when they can be used effectively in the course of disease. It is possible that some therapeutic vaccines would provide effective treatment at later stages of disease, whereas other vaccines would be effective only in early stages. The committee assumed in its analysis that such vaccines are given near to the time of diagnosis; that is, in early disease stages.
An influential factor in the committee’s deliberations about the qualitative inclusion criteria, and in the analytic model, concerns implementation and utilization issues. The committee expects that the report can be useful to vaccine program implementers and policymakers, as well as for the research and development community. The committee has only included vaccines it believes can be important medical and public health tools. However, the committee is cognizant of the concerns of those who will need to plan for the use of the many vaccines that could be licensed in the next 20 years. The chapter concludes with a discussion of implementation issues for children, adults, and pregnant women.
Delivery of Vaccines to Children
The use of vaccines for infant and childhood immunization in the United States is a complex issue, with multiple factors influencing the success of the implementation of the schedules recommended by the Federal Advisory Committee on Immunization Practices and the Committee on Infectious Diseases (“Redbook Committee”) of the American Academy of Pediatrics (AAP). Many studies have investigated the reasons for poor compliance with these schedules and have provided greatly varying conclusions. Issues that are repeatedly en-
countered include the complexity of the vaccination schedule, the costs of the vaccines, problems with access to health care services, the need for multiple injections at a single visit, lack of parental awareness, competing parental priorities, parental complacency, long waiting times in public clinics, lack of reliable transportation, inappropriate interpretation by physicians and other health care workers of contraindications to immunization, missed opportunities for vaccination (at acute care or emergency room visits), poor record keeping, or the unavailability of records, and concerns regarding adverse reactions to vaccines. The single most important determinant of up-to-date vaccination status by the age of 2 years is the presence of an effective primary care system (Guyer et al., 1994).
Children should receive the majority of the recommended immunizations by age 2. In the 1970s, low rates of immunization among 4- to 6-year-old children who were entering school became a concern. Several efforts contributed to increasing immunization rates to well over 95% among this age group. Specifically, all 50 states instituted the requirement that all children must have received all of the recommended immunizations before entering the public school system. In addition, CDC, AAP, and many nongovernmental community-based organizations undertook major efforts to improve immunization rates.
In the 1990s, concern shifted to improving immunization rates among preschool-age children. Coverage rates for some specific vaccines have now risen to over 90% for 2-year-olds, but rates of completion of the full set of recommended immunizations remain below 80% (CDC, 1998). A number of imaginative programs have been undertaken to improve this rate of coverage. Some of the steps include opening public health clinics in the evening and on Saturdays to accommodate families in which both parents are employed or to accommodate single-parent families. Immunization clinics have been established in or near the offices of various federal entitlement programs such as those for the Aid to Families with Dependent Children program and the Supplemental Food Program for Women, Infants and Children. The requirement that an immunization visit include a full health examination has been abandoned in public clinics. Illinois established a program that provided public clinics with a $10 bonus for each child who was up-to-date on the recommended schedule by age 2 years and a $15 bonus for each child if the overall rate of immunization coverage at the clinics was greater than 85%. With this type of stimulation, coverage rates in Illinois have improved markedly (from 75% to 89%) despite the introduction of new vaccines that have further complicated the immunization schedules. Finally, to help make the receipt of multiple immunizations more convenient, some public schools have incorporated immunizations into their school health programs so that preschool-age infants and children may attend neighborhood-school health clinics where school health nurses or other personnel immunize younger cohorts who are not yet attending school.
In attempts to reduce the numbers of required injections, pharmaceutical firms have accelerated R&D on products that combine multiple antigens (diphtheria and tetanus toxoids and acellular pertussis vaccine plus Hib, Hib plus
hepatitis B [HBV], and others yet to come). The increased costs of some of these combination products will be balanced by the eventual reduction in the number of visits required to receive immunizations.
Investments are continuing to be made in the development of vaccines that can be administered by mucosal routes (gastrointestinal or respiratory tract) obviating the need for injections. Although the oral polio virus vaccine remains the only mucosal vaccine in widespread use, licensed vaccines against typhoid and cholera, not to mention the newly licensed vaccine for rotavirus, exemplify the potential of these routes.
In the era of managed care, reimbursement for vaccines and vaccine administration follows a number of different pathways. For some families, health insurance pays. The Vaccines for Children Program provides vaccines for nearly 60% of the nation’s children. More than a dozen states provide free vaccines for all children, whatever their family’s income may be.
In an attempt to overcome the problem of inadequate record keeping, immunization registries have been initiated by a number of states and communities. The registries initially covered public health clinics but have also provided the opportunity for the participation of private providers. It is hoped that registries will help overcome the major problem of a lack of availability of up-to-date immunization records during clinic and office visits. Although concerns regarding the confidentiality of records have been raised, such problems should be amenable to solution. As quality assessment programs are instituted for managed care, the provision of immunization (and other preventive medicine measures) should become a hallmark of quality performance. This too should further ease the problem of families whose current insurance coverage does not include immunization.
Delivery of Vaccines to Adults
The primary care setting is an important site for adult immunizations. In 1992, 85% of influenza immunizations in the United States were administered by private physicians to patients who paid for the vaccine themselves (Fedson, 1995). On the whole, relatively few patients received influenza vaccine from state or local health departments. Several studies have shown that high rates of immunization occur in the office setting whenever patients are offered vaccines during office visits (ACP, 1990). In one study, patient acceptance of vaccination increased 11- to 12-fold when it was recommended by health professionals (Siegel et al., 1990).
Despite the generally favorable attitudes of physicians toward vaccines for adults and evidence that vaccines are cost-effective, major gaps in adult immunization still exist. Although rates of influenza immunization for elderly people have increased nationally, with coverage rates now above 50%, pneumococcal and HBV vaccines are underused (General Accounting Office, 1995; Williams
et al., 1988). Only about one-quarter of high-risk persons have ever received pneumococcal vaccine.
Physician reminders have been shown to be successful in increasing rates of immunization; physicians who received computer-generated reminders vaccinated their eligible high-risk patients twice as often as they vaccinated patients in a control group (McDonald, 1992). A simple reminder sheet completed by the clinician and detailing vaccine eligibility, patient status, and reasons for refusal of the vaccine was successful in significantly increasing the rate of influenza immunization for high-risk outpatients (Merkel, 1994).
An increasing fraction of physicians’ offices in the United States are becoming computerized, and most physicians’ offices are now capable of creating an electronic database for the patients they treat. These systems were originally introduced largely to improve office administration and billing practices, and their role in enhancing the delivery of preventive services has not been well developed.
Such an approach has been tested and has been shown to enhance the delivery of influenza vaccine to elderly people (Bennett et al., 1994). From 1988 to 1991 internists and family practitioners in private practices in Monroe County, New York, participated in a series of demonstration studies to determine whether a target-based approach could increase the rate of influenza immunizations among elderly people. These studies indicate that the rate of immunization can be increased substantially after physicians are made aware of target groups within their practices and are given a simple means of monitoring their rate of coverage (Buffington et al., 1991).
One important logistic hurdle in the comprehensive delivery of influenza vaccine in the office setting is that this vaccine is given during a 3-month period each fall, and eligible patients may not be scheduled to see their physicians during that time. To achieve high immunization rates, physicians must develop initiatives to immunize all eligible patients, not just those who have a visit scheduled during the period when the influenza vaccine is being given.
Hospitals are also important sites for immunization. One of the most effective interventions appears to be the implementation of standing orders for vaccination. This consists of an institutional policy stating that everyone eligible for vaccination is to be vaccinated. Under this protocol, nurses can initiate immunizations without specific orders. Perhaps the best-documented multifactorial hospital-based interventions are those described by Nichol and coworkers (1990) at the Minneapolis Veterans Affairs Medical Center. Programs that ensure that hospitalized patients are immunized with influenza and pneumococcal vaccines are particularly important because two-thirds of the patients hospitalized for pneumococcal infections had been hospitalized within the previous 5 years, and 25% or more of elderly patients admitted for influenza-associated respiratory conditions had been discharged during the immunization season immediately preceding the outbreak period (Fedson, 1987).
Emergency departments can also play an important role in providing influenza and pneumococcal immunizations, especially for people who have no other source of routine medical care. In two studies of emergency departments in university-affiliated hospitals, relatively little effort was required to raise the immunization rates. In one study of emergency department patients, 54% of unvaccinated patients were willing to be immunized when asked (Wrenn et al., 1994). In a second study, about half of elderly patients who were not vaccinated against influenza were vaccinated in the emergency department after receiving information about the vaccine (Rodriguez and Baroff, 1993).
Additional strategies for increasing vaccine use include community-based strategies. Compulsory immunization linked to school attendance has been the single most important strategy for ensuring high rates of childhood immunization among school-age children. School-based programs are also important for the delivery of adult vaccines. The American College Health Association now recommends that all students show records of receipt of vaccinations against measles, mumps, rubella, tetanus, and diphtheria. Some colleges have successfully implemented these recommendations by requiring such evidence before students enroll, before they are given grade reports, or before the transcripts of their records are issued.
Mass immunizations in settings where high-risk patients live have been particularly effective at delivering annual influenza immunizations. An underused approach is the use of Visiting Nurse Associations. Because of their contact with homebound elderly people, these nurses can effectively promote and administer the influenza vaccine. In one Canadian community-based study, public health nurses provided influenza vaccine to elderly people in their homes, at residences for senior citizens, and at well-advertised clinics (Sadoway et al., 1994). They accounted for 69% of the immunizations against influenza that were given, with an overall increase of 26% over the prior year. Potential immunization partnerships that have not been well studied include collaborations with pharmacists, chiropractors, and other health care providers who are outside the more traditional health care delivery systems.
Local health departments can play a major role in coordinating comprehensive efforts at immunizing at-risk populations. During the Medicare Influenza Demonstration Project in Rochester, New York, the Monroe County Health Department (MCHD) took responsibility for coordinating all aspects of vaccine distribution, promotion, and Medicare reimbursement (Bennett et al., 1994). For the duration of the project, proprietary nursing homes were given the option of holding open clinics, and vaccine was released to neighborhood health centers. Special urban outreach clinics were organized in churches, activity centers, and shopping malls. The coordinating role played by MCHD helped ensure that underserved and more vulnerable populations would have access to immunizations.
Encouraging Medicare beneficiaries to take advantage of preventive services is another important strategy. The most effective measures are personalized ones, such as a postcard reminder, particularly if the reminder is followed
up with a telephone call (Pearson and Thompson, 1994). In the Monroe County demonstration, all Medicare beneficiaries received a letter from the Health Care Financing Administration, the federal agency that manages the Medicare program, encouraging all Part B recipients to get a free influenza immunization from their physicians. Other promotional and public health educational efforts have included television, radio, brochures, newspapers, public appearances, and press conferences.
National Health Interview Survey data indicate that African Americans and Hispanics are less likely than whites to have received pneumococcal or influenza vaccine (Centers for Disease Control and Prevention, 1995a). During the Monroe County demonstration, investigators noted low rates of immunization with the influenza vaccine among urban, nonwhite elderly people (Bennett et al., 1994). In response to this problem, MCHD convened a task force composed of representatives from urban churches, health centers, and community-based organizations to develop an action plan to increase the rates of immunization among individuals in this group of underserved Medicare beneficiaries. Partnerships were formed with organizations that could influence members of minority populations who were not receiving vaccination services. Media efforts were targeted toward this underserved population, and special outreach clinics were staffed by members of the African-American senior citizen community. Partnerships were formed with church leaders, who publicly encouraged immunization with the influenza vaccine, distributed educational materials in church bulletins, and assisted in transporting their church members to special clinics located throughout the inner city. The processes used to improve the rates of immunization among individuals in underserved groups are the same as those used among well-served groups in the population. The key difference is the selection of appropriate partners in the immunization outreach effort and ensuring that information is channeled through sources that are used by individuals in the underserved groups.
The examples described above and many others not included here provide convincing evidence that adult immunization programs can be successful if they are well organized and efficiently administered. Nonetheless, such “model” programs are in the minority. Improved immunization strategies, not simply better vaccines, will be required if substantial improvements in adult immunization rates are to be made.
Delivery of Vaccines to Pregnant Women
Immunization of pregnant women against conditions such as neonatal and pregnancy-related group B streptococcal infections has been proposed. Such efforts would eliminate the need for active immunization of infants against some diseases for which susceptibility is limited to young infants, pregnant women, and adults with either defined underlying medical conditions or advanced age.
For most vaccines targeted to pregnant women, vaccination would be given early in the third trimester (28–32 weeks of gestation), a time when organogenesis is complete and when most events associated with adverse pregnancy outcomes have passed. This timing would also theoretically provide protection for many prematurely born infants. Early in the third trimester is also a period when most pregnant women encounter the health care system. Preconceptional or adolescent encounters with the health care system are far less frequent, and efforts targeted at nonpregnancy-related health care visits would result in much lower rates of immunization than efforts targeted at pregnant women in the third trimester.
Because of the exaggerated concerns about the use of vaccines during pregnancy, the most frequent suggestion is to provide immunizations prior to childbearing. This approach requires special access to the health care system, whereas immunization during the third trimester would use existing access mechanisms and assumes that the antibody response would persist for several years at levels ensuring protection for the infant. Many experts have suggested vaccine administration around the age of puberty, and with the recommendation for booster doses of vaccines, including those for measles, mumps, rubella, and tetanus. At this age, an existing medical access system could be used. However, if a girl was immunized at age 12 years with a quadravalent group B streptococcal glycoconjugate vaccine, for example, and had her first pregnancy at age 32 years, several problems would be expected. First, it is unlikely that 20 years later levels of antibodies to this pathogen would be sufficiently high to ensure protection of the infant. Second, a small number of girls would become pregnant before the “adolescent” or “puberty” immunization visits. Third, if proof of vaccine efficacy were to require testing of adolescents and observation through the first pregnancy, the logistics and expense of such a study would likely be an even greater deterrent to the pharmaceutical industry than considering a trial that would immunize women in the third trimester.