TY - JOUR
AU - Roberts, Jeff
AB - Abstract The considerable public health burden due to cytomegalovirus (CMV) supports current interest in vaccine development. Clinical studies intended to support regulatory action should be designed to demonstrate substantial evidence of effectiveness. However, design and conduct of clinical endpoint studies may be hampered by low incidence of disease, especially for congenital CMV. Discussion and experience from other vaccines directed against congenital disease (including rubella and Zika) may be instructive. This article summarizes current scientific and US regulatory considerations related to design of studies of vaccines intended to prevent congenital CMV and complications of CMV in transplantation, as discussed at the 2018 workshop entitled “Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment.” congenital CMV, CMV in transplantation, cytomegalovirus, vaccines The availability of safe and effective vaccines against cytomegalovirus (CMV) in the United States will depend on licensure of such products, which are regulated as biologics by the US Food and Drug Administration (FDA)’s Center for Biologics Evaluation and Research. As companies consider investment in development of these vaccines, it will be important to understand potential pathways to licensure, including the types of clinical trials that could support clinically meaningful indications. Potential gaps in scientific knowledge that could help facilitate development of a CMV vaccine should be considered for future study. This article does not represent FDA guidance, but it does present considerations that may be useful in the design of a CMV clinical development program. The discussion herein is informed by the presentations and discussions at the 2018 workshop entitled “Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment”, which built on the scientific and regulatory considerations discussed at the 2012 CMV Vaccines Workshop [1]. Cytomegalovirus causes can cause serious disease in vulnerable populations—the immunocompromised and the unborn. An effective vaccine that reduced CMV disease in either of these populations could be of significant public health benefit. Recommendations for vaccine use after licensure of one or more indications are the responsibility of the Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Immunization Practices and are not considered here. CONSIDERATIONS FOR VACCINES TO PREVENT CYTOMEGALOVIRUS IN THE IMMUNOCOMPROMISED Background Although CMV infection in individuals with normal immune systems is usually self-limited, CMV can cause serious and even fatal infections in the immunocompromised, most commonly in individuals who receive immunosuppressive medications in association with bone marrow or solid organ transplantation. Due to the dearth of effective treatments for CMV disease, apart from CMV retinitis, which is rare due to effective human immunodeficiency virus treatments, current management of CMV infection in transplantation has focused on use of antivirals to prevent CMV disease, either by prevention of infection or by preemptive therapy given once a low level of infection is detected. The ability of CMV strains to become resistant to antivirals provides additional impetus for development of vaccines, which have mechanisms of action different from those associated with antiviral resistance. Results of clinical efficacy trials in immunocompromised transplant patients have been reported for 3 vaccines: 2 in solid organ transplants (SOT) and the other in hematopoetic stem cell transplant (HSCT) patients. In a phase II study, MF59 oil-in-water emulsion adjuvanted glycoprotein B (gB) vaccine reduced duration of viremia and antiviral treatment in CMV-seronegative subjects receiving SOT from CMV-seropositive donors relative to placebo [2]. In another phase II study, the live-attenuated Towne strain CMV vaccine reduced severity of disease but did not prevent CMV infection in seronegative recipients of renal transplants from seropositive donors [3]. A phase II study of a deoxyribonucleic acid (DNA) vaccine expressing gB and structural protein pp65 suggested promise in renal transplant recipients [4], but a recent phase III study of this vaccine in HSCT transplant patients did not meet its endpoints of reducing overall mortality and CMV end-organ disease, or of time to CMV viremia or first use of CMV-specific antiviral therapy [5]. Hematopoietic Stem Cell Transplants Focusing a clinical trial on the population at greatest risk from CMV will increase the number of disease cases in the placebo group and reduce the size of a study necessary to demonstrate effectiveness. In HSCT transplantation, this is the seropositive recipient (R+) population, because established CMV infection in the recipient is very difficult to control in the setting of immunocompromise, even when the donor immune system is from a seropositive individual. However, because vaccine responses, and ultimately effectiveness, may differ based on serostatus, a vaccine should be tested to address all serostatus combinations intended for licensure. For HSCT, a vaccine would likely be administered before the transplant to the donor to either prime or boost CMV immunity, with possible boosting of immunity in the recipient after transplantation as the transplant engrafts. With the availability of prophylactic and preemptive antiviral treatments (including the recent licensure of letermovir [6, 7]), the incidence of CMV end-organ disease has become rarer in stem cell transplant patients. This makes clinical trials with end-organ disease endpoints less feasible, prompting consideration of other clinically relevant endpoints. Because preemptive therapy is generally triggered by low-level viremia, reduction in the proportion of subjects with CMV viremia or CMV DNAemia at a level that would cause preemptive therapy to be given is a reasonable endpoint for a vaccine clinical trial, recognizing that the exact relevance of any specific level of CMV viremia or DNAemia to current clinical practice may change over time. Ideally, this endpoint would be demonstrated in a central laboratory that tested all samples at the end of the study using an assay cleared by the FDA. Considerations in diagnosing viremia or DNAemia include the need for a clinical trial endpoint to be evaluated using standardized methodology and sample types across multiple clinical trial sites. Solid Organ Transplants In SOT, in which the recipients are not normally immunocompromised before transplant, the greatest risk is in the seropositive donor/seronegative recipient (D+R−) population because the recipient’s unprimed immune system may need to control a significant inoculum of CMV carried in with the transplant. Here, the recipient would likely receive vaccine before transplant, with possible boosters after transplant to maintain longer term immunity. For SOT, CMV disease, defined as either CMV syndrome (fever plus viremia) or tissue invasive CMV disease, occurs frequently enough that these outcomes could be used as a clinical trial endpoints. Other Considerations Mortality was sufficiently frequent in the letermovir study to permit its consideration as an endpoint in vaccine studies of transplant patients [7]. Thus, in addition to the endpoints suggested above, CMV-associated mortality may also be considered either as a component of a primary endpoint or as a key secondary endpoint. Other CMV-associated complications such as graft-versus-host disease might also be considered as components of clinical trial endpoints, recognizing that this approach could lead to inclusion of cases unrelated to CMV. Because there would be no expectation that non-CMV-associated outcomes would be influenced by a CMV vaccine, this would reduce case specificity and increase risk that the study would fail to demonstrate efficacy. However, this risk could be mitigated by powering the study based on an appropriately revised point estimate for efficacy. In addition, evidence that the vaccine could reduce the rates of important potential complications such as graft-versus-host disease would be clinically significant. Because no CMV vaccine is currently licensed and use of a vaccine would not preclude use of other treatments, efficacy studies can be randomized, blinded, and include placebo controls. In the absence of compelling rationale for a different approach, vaccine studies should be conducted on a background of current standard-of-care, including antiviral drugs that are used in the transplantation setting. A vaccine that improved clinical outcomes, including decreasing the need for preemptive treatment, could be considered as an adjunct to existing prophylactic antiviral drugs, or it might substitute for existing prophylactic antiviral regimens, with the potential clinical advantage of fewer side effects. The FDA’s Center for Drug Evaluation and Research recently published a draft guidance on “Cytomegalovirus in Transplantation: Developing Drugs to Treat or Prevent Disease” [8]. Although this guidance is not directly applicable to vaccines and is not a final guidance (having been distributed for comment purposes only), the document suggests endpoints for trials of drugs (including monoclonal antibodies) intended to prevent CMV after transplantation consistent with those that have been considered for use in studies of vaccines [1]. CONSIDERATIONS FOR CYTOMEGALOVIRUS (CMV) VACCINES TO PREVENT CONGENITAL CMV Background Congenital CMV disease (cCMVd) is considered one of the major targets for a CMV vaccine, based on the substantial public and individual health benefits that could be attained if a vaccine would significantly reduce the associated disease burden. Designing a clinical development program to demonstrate that a vaccine can directly prevent cCMVd is complex, considering the need to connect vaccination of mothers with outcomes in their infants. The rarity of cCMVd also increases the difficulty of performing studies with this endpoint. Some aspects of recent discussions of Zika vaccine evaluation may be applicable to CMV, because both viruses are rare causes of congenital disease [9]. Confidence in vaccine effectiveness is greatest when clinical trials are randomized, controlled, and double-blind, with clinically meaningful endpoints. In general, the need for a high level of confidence in vaccine efficacy implies that the statistical lower confidence bound on vaccine efficacy should be considerably above zero, or that more than one clinical trial should independently provide support for a conclusion of vaccine efficacy. Confidence in vaccine efficacy also is bolstered when vaccine effect is shown on more than one relevant endpoint. The need for large sample sizes to meet these criteria can increase the difficulty of designing clinical programs to evaluate vaccines targeted against uncommon diseases. Moreover, licensed vaccine indications typically correspond to the actual clinical endpoint of the prelicensure clinical trials, which would suggest difficulty in obtaining a vaccine indication against uncommon diseases. However, the FDA may grant “traditional approval” for a vaccine indication based on a scientifically well established marker of protection, or, if several additional conditions are met, it may grant “accelerated approval” (subject to postlicensure confirmatory studies) based on a “surrogate endpoint that is reasonably likely… to predict clinical benefit” [10]. Thus, available regulatory pathways can be used to address the possibility that preventing congenital disease cannot be directly demonstrated before licensure, with important differences between “traditional” and “accelerated” approval, including (1) the level of evidence supporting the relationship between the study endpoint and the indication at the time of approval and (2) the requirement for a confirmatory study after accelerated approval. Study Populations and Clinical Trial Endpoints Because cCMVd is rare and may not become clinically apparent for years after birth of a child, efficacy trials using this endpoint seem to be infeasible. At the 2012 CMV Vaccine Workshop, participants noted that prevention of congenital CMV infection (cCMVi) would be a strong predictor of prevention of cCMVd [1]. Use of a cCMVi endpoint would still require following a vaccinee through pregnancy to determine whether she delivered an infected baby (or whether there was other evidence of cCMVi in association with the pregnancy), but an initial determination of efficacy would not require further follow-up of the baby to evaluate how cCMVd evolved. However, the incidence even of cCMVi is also sufficiently rare that it may be difficult to design a study with adequate power to evaluate this endpoint with a lower confidence bound substantially higher than zero. This situation has led to consideration of more readily evaluable endpoints that could predict congenital disease or infection. One endpoint that might be considered is prevention of maternal CMV infection (mCMVi), based on the reasoning that prevention of mCMVi likely would lead to prevention of cCMVi, which likely would predict prevention of cCMVd. Because maternal infections are far more common than congenital infections and maternal infection is a prerequisite for congenital infection, use of a maternal infection endpoint would substantially reduce the sample size needed to demonstrate vaccine efficacy. In addition, even if there were no demonstration of benefit against cCMVd, a vaccine that reduced mCMVi would likely lead to reduced elective terminations of pregnancies, because detection of maternal infection, even as an isolated laboratory finding, can result in a decision to terminate. Previous trials of CMV vaccines have used prevention of primary CMV infection in mothers or prospective mothers as endpoints. A randomized placebo-controlled trial of a recombinant CMV envelope gB vaccine formulated with MF59 reported 50% efficacy in preventing acquisition of primary CMV infection in young mothers [11]. In a different study, the same vaccine was 43% effective in preventing CMV infection in seronegative adolescent girls [12]. One concern about use of mCMVi as an endpoint is that a moderately effective vaccine might protect only against the (presumably less severe) subset of mCMVi that would not ultimately lead to cCMVi and cCMVd, and thus effectiveness against mCMVi might not predict effectiveness against cCMVi or cCMVd for vaccines that are not highly efficacious. However, experience with other vaccines, which are generally more effective against severe than mild disease, suggests that this outcome is improbable. A clinical trial could include secondary endpoints to systematically evaluate the unlikely possibility that the demonstration of vaccine efficacy could be dominated by reduction in rates of “milder” mCMVi with little or no impact on more “severe” mCMVi. Very high vaccine efficacy against mCMVi in pregnant women would further increase the likelihood that the vaccine would also be effective in preventing cCMVi and cCMVd, suggesting that, if there were uncertainty regarding the connection between mCMVi and cCMVi due to this concern, demonstration of effectiveness against mCMVi using a stringent lower confidence bound would increase the likelihood of effectiveness against cCMVd. As a clinical trial endpoint, prevention of mCMVi has the significant disadvantage that complete protection from infection by vaccines is usually difficult to achieve, especially as time elapses after vaccination [1]. Thus, although prevention of mCMVi may be an attractive endpoint to consider because cases will be relatively more frequent, leading to the appearance of adequate study power at lower overall sample sizes, it may not be as achievable from a vaccine performance perspective. It is plausible that a vaccine that reduced the severity of maternal infection without completely preventing maternal infection could also reduce the incidence of congenital disease, even without completely protecting against maternal infection. Thus, a requirement that a vaccine show a high level of protection against an mCMVi endpoint may bias a clinical development strategy against a vaccine that is nonetheless effective against cCMVd. In design of a trial with an mCMVi infection endpoint, it would be important to specify how maternal infection will be ascertained. Development of new antibody responses (eg, immunoglobulin M responses) to CMV antigens may be the simplest approach to diagnosis of new infections, but this approach would depend upon the postvaccination immune response being clearly distinguishable from that observed after infection, which will in turn depend on which CMV antigens are included in the vaccine. It may be difficult or impossible to distinguish vaccine responses from newly acquired infections in individuals who are CMV-seropositive before vaccination. Alternatively, other methods could be used to detect symptomatic or asymptomatic infections. For example, in evaluation of Zika vaccines, consideration has been given to identification of infection by testing of serial urine specimens [9]. If considered for CMV, such an endpoint would need to be validated for diagnosis of CMV infection in the context of a clinical trial. Potential drawbacks of mCMVi, cCMVi, and cCMVd clinical study endpoints suggest the value of considering additional endpoints that may both predict effectiveness against cCMVd and be more feasible for evaluation in a clinical trial. It is plausible, but unproven, that significant improvement in the severity of maternal infection could reduce the likelihood of congenital infection. If feasible to obtain, clinical data that supported a relationship between cCMVi and either symptomatic mCMVi or a lower level of viremia in association with mCMVi could aid in supporting the use of such clinical endpoints. It would be prudent to collect as much information on severity of maternal infection as possible in future CMV vaccine clinical trials and other studies, so that such a correlation, if it exists, could be used to support an endpoint in subsequent studies of vaccine effectiveness, recognizing that if cCMVi were too rare to evaluate a vaccine effect, it may also be too rare to conclusively demonstrate that severity of mCMVd predicts protection from cCMVd or cCMVin. An alternative to using clinical disease outcomes as clinical trial endpoints would be to identify a laboratory-based surrogate marker, likely based on immune response, that could predict congenital infection. The potential role of anti-CMV antibodies in preventing cCMVi in infected mothers is intriguing, but caution is warranted, given the equivocal results in studies of CMV-specific hyperimmune globulin administered during pregnancy [13]. Justification of a “protective” antibody titer cutoff based on clinical correlation between likelihood of cCMVi and antibody titers in women with previous wild-type CMV infection may not be persuasive, because the relative importance of humoral and cellular immunity in protecting against cCMV is unknown. Hampering this effort is the lack of an animal model for human CMV infection, which may require supportive animal work to be done with related animal species-specific viruses. To achieve the desired benefit against cCMVd, a CMV vaccine would need to be deployed in a way to reduce the incidence of infection capable of transmitting the virus to neonates. Recent changes to the National Vaccine Injury Compensation program now provide coverage for injuries to pregnant women or their children as a result of CDC-recommended vaccines administered during pregnancy [14], which overcomes one challenge to development of a CMV vaccine for use during pregnancy. However, given that many pregnancies are not immediately identified, cCMVi can occur early in pregnancy (and indeed first trimester primary infections are most likely to lead to sequelae [15]), and most vaccines are expected to require some time to induce optimal immunity, it seems unlikely that vaccination of pregnant women would be an effective strategy. Thus, women or adolescents will likely need to be vaccinated before they become pregnant. Because the timing of pregnancy is usually unpredictable, this suggests that a vaccine would need to have a duration of efficacy of several years or more. If a vaccine were deployed in adolescent girls, pregnancy could be many years later. Mothers, particularly those who have children in daycare, have a higher likelihood of contracting primary mCMVi during a subsequent pregnancy, and thus they will likely experience higher infection rates if enrolled in a clinical study, which could increase study power. Consideration should be given to other “herd immunity” based strategies for protecting against congenital CMV. Indeed, congenital rubella was not adequately addressed by immunization only of adolescent females; ultimately, control required immunization of both sexes and making rubella immunization a childhood vaccine to address infant to mother transmission of the virus [16]. The analogy with rubella suggests that it may be reasonable to consider developing a CMV vaccine for toddlers, with the expectation that it would reduce infection and/or viral shedding in this group. The ability of a vaccine to influence viral shedding or transmission to close contacts could be directly studied. Because CMV disease is not currently considered a major problem in toddlers, acceptance of such an approach might be facilitated by (1) additional study into the burden of CMV illness in this age group or (2) improved understanding of the lifelong impact of CMV infection. Data indicating that a vaccine could prevent transmission from toddlers to other individuals, including their mothers, could support the use of a toddler vaccine to reduce the incidence of cCMVd. Other Considerations Serostatus may influence both vaccine responses and potential utility of vaccine response against the background of previously existing immunity. Despite the fact that an effective vaccine might have substantial benefit when given to mothers who were seropositive before becoming pregnant, because they are the source of most cCMV transmissions in many locations [17], the significantly lower rate of cCMV in children of seropositive versus seronegative mothers makes an efficacy study against cCMVi even more difficult to carry out in seropositive women. Thus, for a congenital CMV indication, it seems likely that there would be direct efficacy data only in seronegative women. Although it is still not clear what proportion of cCMVd cases are transmitted as a result of primary infection versus secondary infection (with a new strain acquired during pregnancy) versus reactivation of latent infection in the mother, it seems reasonable to assume that direct vaccine impact would be maximized if immunization occurred at ages before individuals become seropositive. If vaccines were ultimately deployed at ages at which there are a high proportion of seropositives, there may be some utility in serological testing to identify those who are likely to benefit most from vaccine, although if there were no safety issue with vaccinating seropositives, use without serological testing of a vaccine known to be beneficial only in seronegatives could also be contemplated. Although deployment of vaccine at an age at which there are significant numbers of seropositives likely would be safe, it may be that demonstration of benefit would be most convincing if the vaccine were deployed at an age before many girls or women become seropositive. If a vaccine were approved under the FDA’s accelerated approval regulations, indicating a reasonable likelihood of clinical benefit, there would be a requirement for a confirmatory study. Even in the absence of a requirement to confirm benefit against cCMVd, vaccine- recommending bodies may request such data before making firm recommendations in favor of vaccination. If mCMVi were the clinical trial primary endpoint, it may be possible to also evaluate efficacy against cCMVi as a confirmatory endpoint in the same trial. However, once a vaccine is licensed (regardless of regulatory pathway), it becomes difficult to continue or initiate placebo-controlled studies. Recent discussions have contemplated the use of “real-world evidence,” or RWE (which can include evidence generated from observational studies), to confirm vaccine effectiveness when confirmatory studies are not otherwise feasible. Although observational studies are subject to various biases, and the FDA policy on consideration of RWE studies is still under development, the Vaccines and Related Biological Products Advisory Committee discussed use of RWE studies to confirm benefit of maternal immunization to protect an infant from disease [18], and use of RWE studies to evaluate congenital infection outcomes has been discussed in the context of Zika vaccines [19]. RWE approaches have also been used to study effectiveness and duration of benefit of zoster vaccines [20] and effectiveness of influenza vaccines [21]. If RWE studies were to be contemplated for confirmation of vaccine benefit, design and implementation of these studies would face considerable logistical challenges, including linking records of maternal immunization with cCMVd in the child. Routine screening of newborns to detect congenital CMV could facilitate design and conduct of such studies. Use of RWE studies to support effectiveness in a regulatory setting likely will depend on the availability of supporting documentation, as well as study design and results, and ideally would be based on prospective discussion and agreement with regulators regarding the conditions under which any specific RWE study could support regulatory actions. CONCLUSIONS The considerations presented here (summarized in Table 1) represent current thinking on strategies for obtaining effectiveness data to support CMV vaccine licensure and are not intended to be exhaustive. Because each product and associated considerations are likely to be different, US regulators welcome discussion with sponsors about design of clinical trials to evaluate CMV vaccines. Table 1. Populations and Endpoints for Studies of Cytomegalovirus Vaccines CMV Disease . Population to Immunize . Possible Endpoints . Considerations . Immunocompromised SOT recipients CMV syndrome + end-organ disease D+R− at greatest risk HSCT donors and recipients CMV viremia inducing preemptive therapy R+ at greatest risk Congenital CMV Prepregnant women cCMVd Study power and vaccine efficacy cCMVi mCMVi Others Adolescent girls Similar considerations to prepregnant women Duration of effectiveness Toddlers CMV disease, infection, transmission, and shedding Unclear whether vaccine would be used or recommended CMV Disease . Population to Immunize . Possible Endpoints . Considerations . Immunocompromised SOT recipients CMV syndrome + end-organ disease D+R− at greatest risk HSCT donors and recipients CMV viremia inducing preemptive therapy R+ at greatest risk Congenital CMV Prepregnant women cCMVd Study power and vaccine efficacy cCMVi mCMVi Others Adolescent girls Similar considerations to prepregnant women Duration of effectiveness Toddlers CMV disease, infection, transmission, and shedding Unclear whether vaccine would be used or recommended Abbreviations: cCMVd, congenital cytomegalovirus disease; cCMVi, congenital cytomegalovirus infection; CMV, cytomegalovirus; mCMVi, maternal CMV infection; D+R−, donor seropositive/recipient seronegative; D−R+, donor seronegative/recipient seropositive; HSCT, hematopoietic stem cell stransplant; SOT, solid organ transplant. Open in new tab Table 1. Populations and Endpoints for Studies of Cytomegalovirus Vaccines CMV Disease . Population to Immunize . Possible Endpoints . Considerations . Immunocompromised SOT recipients CMV syndrome + end-organ disease D+R− at greatest risk HSCT donors and recipients CMV viremia inducing preemptive therapy R+ at greatest risk Congenital CMV Prepregnant women cCMVd Study power and vaccine efficacy cCMVi mCMVi Others Adolescent girls Similar considerations to prepregnant women Duration of effectiveness Toddlers CMV disease, infection, transmission, and shedding Unclear whether vaccine would be used or recommended CMV Disease . Population to Immunize . Possible Endpoints . Considerations . Immunocompromised SOT recipients CMV syndrome + end-organ disease D+R− at greatest risk HSCT donors and recipients CMV viremia inducing preemptive therapy R+ at greatest risk Congenital CMV Prepregnant women cCMVd Study power and vaccine efficacy cCMVi mCMVi Others Adolescent girls Similar considerations to prepregnant women Duration of effectiveness Toddlers CMV disease, infection, transmission, and shedding Unclear whether vaccine would be used or recommended Abbreviations: cCMVd, congenital cytomegalovirus disease; cCMVi, congenital cytomegalovirus infection; CMV, cytomegalovirus; mCMVi, maternal CMV infection; D+R−, donor seropositive/recipient seronegative; D−R+, donor seronegative/recipient seropositive; HSCT, hematopoietic stem cell stransplant; SOT, solid organ transplant. Open in new tab Notes Presented in part: Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment meeting, Rockville, Maryland, 4 September 2018. Acknowledgments. 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TI - Scientific and Regulatory Considerations for Efficacy Studies of Cytomegalovirus Vaccines
JF - The Journal of Infectious Diseases
DO - 10.1093/infdis/jiz523
DA - 2020-03-05
UR - https://www.deepdyve.com/lp/oxford-university-press/scientific-and-regulatory-considerations-for-efficacy-studies-of-xK0LIc4JGB
SP - S103
EP - S108
VL - 221
IS - Supplement_1
DP - DeepDyve
ER -