When Dr. Martin Randolph came to Danbury, a small city in the southwestern ­corner of Connecticut, in 1948, the medical establishment there was ill prepared for this young, energetic, academic pediatrician. In this former “hat city”—so named because a large proportion of America’s hats were made there in the early twentieth century—general practitioners practiced everything from pediatrics to surgery. Randolph was a different breed—the first board certified pediatrician in Danbury—who continued his research on new treatments and vaccines while maintaining a busy private practice out of his home office.¹

Randolph successfully advocated for the widespread adoption of the new ­vaccines—as they became available in the 1950s and 1960s—against polio, measles, and mumps in children. By the early 1970s, he was the health advisor to the public and parochial schools and in this capacity, through his academic ties to nearby Yale and with the backing of his brother-in-law—the city’s director of health, he was able to attract research studies to Danbury.²

Fresh off the success of the meningococcal vaccine work at WRAIR, Goldschneider—now a civilian—had relocated to the University of Connecticut Medical Center, a monolithic structure arising from a hilltop on the 106-acre O’Meara farm tract in suburban Hartford that had opened its doors shortly before he arrived. There, he met Martha Lepow, a pediatric infectious diseases researcher with a track record in vaccine studies. Together, they decided “it was time to take meningococcal A and C vaccines to the kids”.³

Lepow possessed a vaccine researcher’s pedigree. After graduating from medical school in 1952, she had studied viruses in the laboratory of Fred Robbins at Case Western in Cleveland. Robbins, as we saw, shared the 1954 Nobel Prize with Enders and Weller for their landmark work in growing polioviruses in tissue culture—research that led directly to an effective vaccine against polio. Lepow became enamored with laboratory research there, deciding to make it a major part of her career. With her husband, who was recruited to be the Chair of Pathology, she joined the fledgling University of Connecticut Medical Center in 1967, launching the discipline of pediatric infectious diseases there and initiating a decade-long effort to advance the health of children by focusing on disease prevention using vaccines. Moving to Albany Medical School in 1978, she continued that mission—as she does there today—at the age of 85.

Goldschneider’s original work at WRAIR on the natural course of immunity to the meningococcus in humans had shown that the most vulnerable period for the development of meningococcal meningitis was in young children between the ages of six months and two years; after that, there was a progressive decline in the number of cases except for a small blip in the rate that occurred in the young adult years—coincident with military service.⁴ What the WRAIR investigators found most interesting, though, was the inverse—opposite—relationship between levels of serum antibody directed against the polysaccharide capsule and the number of meningitis cases; as the levels of antibody progressively rose, beginning in two-year-olds, the occurrence of disease rapidly decreased. As we have seen, by the late teens, most people had developed immunity to at least some strains of the meningococcus. By that time, those lacking immunity against an epidemic strain were at high risk of getting meningococcal meningitis in basic training or a similar setting.

Given this pattern, meningococcal infection appeared to behave similarly to other classic infections of childhood. Even before the availability of vaccinations for measles, polio, and diphtheria, all of these infections were known to be significantly more common at young ages. Case rates of these diseases, extremely low during the first six months of life, increased during early childhood and then began to decline after two years of age—around the same time that many children developed antibodies in their blood—through natural exposures or actual illness—to ward off the germ. Thus, naturally acquired antibody, even without clinical manifestations of disease, appeared to prevent infection against these pathogens. In fact, a twist on this concept—provoking the formation of protective antibodies by challenging children with weakened versions or proteins of a germ—was harnessed to create successful vaccines against these childhood scourges.

Why were there so few cases of the classic diseases of childhood or meningococcal meningitis during the first six months of life? That answer had begun to be understood shortly before the WRAIR group began their initial investigations. Neonates—newborn babies—have essentially no ability to generate their own immune responses against a world filled with potential, dangerous infectious threats. Fortunately though, they are the recipients of a final gift from their mothers before birth; antibodies from her blood are transferred through the placenta to the fetus. These represent a sampling from the mother’s entire repertoire of antibodies against various infections—generated by numerous exposures or actual infections over the course of her lifetime—that can now be used to protect her newborn from these same problems. But the catch is they only persist for about six months; after that, the child must either make their own antibody upon exposure to a particular germ or be artificially exposed by virtue of vaccination. The inherent downside of natural exposure to these pathogens, of course, is that it will sometimes result in severe illness.

Armed with an understanding of the process of immunity to meningococci gleaned from the WRAIR studies, Lepow and Goldschneider developed plans for vaccine trials in children. With group C and group A meningococcal vaccines provided by the Army via their contracted manufacturer—E.R. Squibb—they ­performed two, small pilot studies.

Twenty-two children of University of Connecticut faculty members, including Lepow’s two sons and Goldschneider’s eldest one, were administered group A meningococcal vaccine, which had already been tested in 600 military recruits and was found to be safe and capable of inducing antibodies against the bacteria.⁵ The Army had not performed a large-scale clinical trial with this vaccine—as they had with group C vaccine—because there were too few cases of natural group A meningitis in the recruit camps to be able to measure whether the vaccine was protective. Twenty-six children, residents of nearby Newington Children’s Hospital who ranged in age from seven months to nine years and had parental consent, were vaccinated with the group C vaccine. At Newington, a facility specializing in the care of children with chronic orthopedic and neurologic disabilities resulting from conditions such as Legg–Perthes disease, a congenital hip deformity; scoliosis, an abnormal curvature of the backbone; and various abnormalities of the spinal cord, the pediatric recipients could be closely monitored by the medical staff.⁶ The results—the vaccine was safe from serious side effects and provoked an appropriate antibody response in the kids—were encouraging to the investigators, prompting a larger study.

The next step was to study the vaccine in younger children on a larger scale to determine its potential effectiveness in a pediatric population—of vital importance because of the high risk of disease in this group. They got permission to test the Army vaccine, and through Goldschneider’s connections, they were able to obtain a supply—then only available to the military.⁵ Using the successful model employed by Jonas Salk, who had executed the massive, national polio vaccine trial in elementary schools nearly two decades earlier, Lepow initially approached the West Hartford school superintendent in early 1972 and proposed to study first and second graders in the district where her children attended school.³ She was rebuffed on the basis that “we do not do research in our schools.” Undeterred, they would not have to look much farther afield to find their trial site.

Randolph, still actively engaged in academic medicine while juggling a busy, 100-hours per week solo pediatric practice, was in the audience in the early part of 1972 to hear Goldschneider and Lepow give a presentation on meningococcal vaccine research at Yale’s pediatric grand rounds. In it they described their desire to perform a large clinical trial to study the effectiveness of the meningococcal A and C vaccines in young children. Afterwards, Randolph—the health advisor to Danbury’s schools—approached the speakers with a proposal; he thought that he could arrange for them to perform the trial in Danbury because there, “the schools, the parents and the city in general, knew of the benefits from medical research and had become accustomed to trials of new vaccines”.² To his everlasting credit, he made it happen.