STUDY POPULATION AND STOPPING RECOMMENDATION
Enrollment took place from August 1999 through April 2006. A total of 464 seronegative subjects underwent randomization. Of these subjects, 23 (9 in the vaccine group and 14 in the placebo group) were excluded because they did not meet inclusion criteria on the day of enrollment. Among the remaining 441 subjects, some subjects did not receive all three planned injections for a variety of reasons (). For a 14-month interval after Sanofi Pasteur acquired the rights to the study vaccine from Chiron (now Novartis), the study vaccine was unavailable while the manufacturer established procedures for monitoring vaccine stability. There were no significant differences between the two groups in any of the baseline characteristics ().
Baseline Characteristics of the Subjects
After the second scheduled interim review of efficacy results, the data and safety monitoring board reported that the vaccine was superior to placebo and had crossed the preset boundary (P = 0.0197) for statistical significance. The board recommended that the study continue under blinded conditions until all subjects had been followed for at least 6 months after the final dose of a study vaccine. When that milestone was met in April 2007, 99 subjects in each group had completed all study visits; 75 in the vaccine group and 64 in the placebo group were still in follow-up. A total of 51 of 225 vaccine recipients (23%) dropped out of the study before completion of the trial, as did 53 of 216 placebo recipients (25%). There were no significant differences between the two groups in the rate of early termination (P = 0.64) or in the time to early termination (P = 0.65 by Kaplan-Meier analysis and the log-rank test). Reasons for early termination in the vaccine group were loss to follow-up (28 subjects), adverse events (3 subjects), withdrawal (9 subjects), and noncompliance (11 subjects). In the placebo group, the reasons were loss to follow-up (39 subjects), withdrawal (7 subjects), and noncompliance (7 subjects). At the time of the review by the data and safety monitoring board, 49 end points had been detected; by the time the data set was closed in June 2007, 1 additional CMV infection had occurred in each group.
A total of 19 CMV infections occurred in the vaccine group and 32 in the placebo group. None of the infections were diagnosed medically, and no subjects had symptoms that were suggestive of a mononucleosis-like illness during the interval of seroconversion. Infection was confirmed by the detection of CMV in body fluids by culture, PCR, or both in all but two subjects. In these two subjects (both in the vaccine group), immunoblots showed the presence of antibody against two or more non-glycoprotein B proteins, confirming infection. Two CMV infections (one in each group) occurred after subjects had completed the 42-month follow-up schedule. These subjects were pregnant at their termination visit and were followed, per protocol, to determine the outcome of the pregnancy. Because only pregnant subjects were followed beyond 42 months, efficacy calculations were censored at 42 months, so 49 subjects were included in the efficacy analysis, 18 in the vaccine group and 31 in the placebo group.
Vaccine recipients were more likely to remain uninfected than placebo recipients (P = 0.02) (). CMV infection occurred in 18 of 225 subjects in the vaccine group (8%) and in 31 of 216 subjects in the placebo group (14%). Rates of infection per 100 person-years were 3.3 in the vaccine group and 6.6 in the placebo group, for an overall vaccine efficacy of 50% (95% confidence interval [CI], 7 to 73). In addition to the characteristics listed in , the following variables were assessed with the use of Cox proportional-hazards regression: the type of regimen (vaccine or placebo), the number of days between screening and enrollment, the occurrence of pregnancy during the study, height, the number of doses of vaccine received, and the presence in the home of children under 13 months of age, from 13 to 36 months of age, and between 37 and 72 months of age. The regimen was the only covariate that had a P value of less than 0.05 in the univariate model. Age, race, height, and the presence in the home of children from 13 to 36 months of age had P values of 0.25 or less and were included in a multivariate proportional-hazards model. The type of regimen was the only variable that was significant in this model (P = 0.02), with a hazard ratio in the vaccine group of 0.51 (95% CI, 0.29 to 0.92).
Kaplan-Meier Estimates of Probability of Remaining Free of CMV Infection
OUTCOME OF PREGNANCIES
A greater proportion of subjects in the placebo group than in the vaccine group became pregnant during the trial (P = 0.04) (). There were no significant differences between the two groups in the time to pregnancy (according to Kaplan-Meier analysis) or in any of the pregnancy outcome variables shown in . The mean (±SD) birth weights of infants were similar in the two study groups (3193±65 g in the vaccine group and 3178±68 g in the placebo group). Congenital CMV infection was detected in 1 of 81 infants born to mothers in the vaccine group (1%) and in 3 of 97 infants born to mothers in the placebo group (3%, P = 0.41). All congenital infections were the result of maternal infection during pregnancy. One infected newborn in the placebo group had severe symptomatic congenital CMV infection with microcephaly, intracranial calcifications, and thrombocytopenia; follow-up revealed delayed psychomotor development. The other three infants with congenital CMV infection were asymptomatic at birth and were free of sequelae 3 to 5 years later. The congenitally infected newborn of a mother in the vaccine group was born 8 months after the subject had completed her study termination visit and 50 months after the first dose of vaccine.
Outcome of Pregnancy during the Study Period*
There were no significant differences between the vaccine group and the placebo group in the frequency of fever, headache, nausea, fatigue, or rash after the first, second, or third doses of a study vaccine. Arthralgias occurred significantly more frequently in the vaccine group but only after the third dose (10 of 176 subjects in the vaccine group [6%] vs. 1 of 159 subjects in the placebo group [1%], P = 0.03). Similarly, chills occurred significantly more often in vaccine recipients than in placebo recipients but only after the third dose (14 of 176 subjects in the vaccine group [8%] vs. 2 of 159 subjects in the placebo group [1%], P = 0.01). The rate of myalgias was greater in the vaccine group than in the placebo group after the first dose (36 of 228 subjects [16%] vs. 13 of 225 subjects [6%], P = 0.007) and after the third dose (28 of 176 subjects [16%] vs. 5 of 159 subjects [3%], P = 0.001). The majority of all systemic reactions were mild. The only systemic reaction for which there was a significant difference in the duration of symptoms was headache, which was of longer duration in the placebo group than in the vaccine group after the second dose. The median duration for most reactions was less than 1 day.
Local reactions at the site of injection within 7 days after immunization occurred more often in the vaccine group (). After the third dose of vaccine, 3% of subjects in the vaccine group reported severe pain, and 2% reported severe erythema; for all other injection-site reactions, the proportion of subjects in the vaccine group who reported having severe symptoms was 1% or less. In the placebo group, only one subject reported severe pain after the first dose, and there were no other severe local reactions. The majority of all local reactions lasted less than 1 day, and there was no significant between-group difference in the duration of symptoms, with the exception of pain at the injection site (for all three doses) and warmth and erythema (for the third dose only).
Rates of Injection-Site Reactions of Any Severity, According to the Number of Doses Administered*
There were no significant differences between the vaccine group and the placebo group in overall rates of adverse events, in adverse events that were at least moderate in severity, or in serious adverse events in the subjects or their infants born during the study (). Adverse events that were considered to be possibly related to a study vaccine occurred in 16 of 231 subjects in the vaccine group (7%) and in 4 of 226 subjects in the placebo group (2%, P=0.01). The nonspecific character of the possibly related adverse events (which are listed in the footnote to ) suggests that CMV glycoprotein B vaccine with MF59 adjuvant has systemic reactogenicity in a small percentage of subjects that was not captured by the systemic reactions listed on diary cards.
Rates of Adverse Events and Serious Adverse Events*
Two serious adverse events were considered possibly related to a study drug. One subject in the vaccine group had fever, myalgia, weakness (unable to walk), and rash 8 days after the second dose of vaccine; she recovered fully over a period of 6 to 7 months. One subject in the placebo group had peripheral neuropathy characterized by numbness and paresthesia affecting her feet and hands 10 weeks after the second dose of vaccine. An extensive neurologic evaluation was not able to identify a cause. Her symptoms improved substantially but had not completely cleared at the end of the study. Serious adverse events were noted in seven newborns (eight events) of mothers in the vaccine group and in eight newborns (eight events) of mothers in the placebo group. The affected babies were conceived 3 to 40 months after the last dose of a study vaccine was administered.