Meningococcal C vaccine program answers up in United Kingdom

CHICAGO — It is not unusual for biological products, vaccines especially, to be held to the rigors of clinical trials before they are licensed for public use.

But what happens when public concern about a disease is so great that the governing body demands that the bureau of health rapidly and successfully introduce a product that will reduce disease and death?

In the United Kingdom, it meant that the Communicable Disease Surveillance Center of the Public Health Laboratory Service had to go out and find a manufacturer to produce a meningococcal C conjugate vaccine for widescale use among young children and teenagers.

Since public concern was at a feverish pitch and the media was publicly chastising the government and health department for a failure to control meningitis outbreaks, it also meant the Medicines Control Agency, the U.K.’s regulatory body, had to agree to license a product that had never been field tested for efficacy.

If the venture had failed, and the vaccine did not adequately protect against disease, the onus would have fallen solely on the Communicable Disease Surveillance Center. In an era of intense media scrutiny, the center either had to come through or face public humiliation.

But, almost three years later, the critics have been largely silenced by the successful implementation of a vaccine program that has reduced disease not only in vaccinated individuals but also among unvaccinated individuals as well.

While meningococcal disease has not been eliminated in the United Kingdom, the success of the vaccine program has quelled public panic and restored confidence in the Public Health Laboratory Service.

Public pressure

Prior to 1994, meningococcal group C cases had flatlined in the United Kingdom at approximately 300 cases a year. But a new clone, C2A, started to emerge, and it was associated with a high mortality rate.

Although serogroup B is the predominant disease causing serotype in the U.K., school-related outbreaks of type C Neisseria meningitides garnered more media attention. As children died from what the press was calling the “deadly brain disease,” the public and the government called on the Public Health Laboratory to take action.

The British parliament issued a direct demand to the Communicable Disease Surveillance Center to begin widescale vaccination with meningococcal C polysaccharide vaccine, as had been done in Canada and Spain.

However, because the polysaccharide formulation provides only a short duration of protection it has a propensity to cause hyper-responsiveness, therefore potentially affecting vaccine efficacy of subsequent doses. Because the vaccine provided no protection to the youngest population, that idea was rejected, said Elizabeth Miller, MD, head of the immunization division at the center.

Instead, the center turned to the private sector. In what Miller called a “true partnership between the public and private sector,” several conjugate vaccine candidates were brought forth for consideration. The only problem was there was not time to subject the vaccines to rigorous clinical trials.

Using data from a series of trials on the correlates of protection among U.S. military recruits in the late 1960s, the Medicines Control Agency decided to approve the vaccine anyway. In those trials, researchers showed that detectable serobactericidal antibody at a titer of >1:4, using a human complement, was adequate to generate protection against meningitis.

The U.K. licensing body, using a rabbit complement, was able to show that the candidate conjugate vaccine produced by Wyeth generated protection at titers >1:8.

Two-tiered introduction

The vaccine was approved in July 1999. With the winter months fast approaching, and that being the time when meningitis cases are most prevalent, the department had to act fast to get the public vaccinated. However, while the government was demanding universal vaccination of everyone 18 and younger, requiring some 12 million doses of vaccine, the center had just 3 million doses ready.

At the time, the disease incidence was highest in the first few years of life followed by a second peak among adolescents due in large part to school-related outbreaks. So, instead of spreading supply thin, and potentially missing children at high-risk, the center decided on a tiered introduction.

Source: Adapted from data compiled by the Public Health Laboratory Service, U.K.

The plan, according to Miller, was to start vaccinating 15- to 17-year-olds with a single dose of vaccine and to start a three dose routine series with 2-month-olds. Children receiving the diphtheria-tetanus-acellular pertussis vaccine, which in the U.K. is given at 2, 3 and 4 months of age, would also receive a meningococcal conjugate C vaccine dose.

For children between 4 and 11 months of age, a two-dose catch-up schedule was devised. As supply increased, Miller said, vaccine indications were added to include other children younger than 18.

Cases of group C meningitis fell off immediately, with cases dropping from 954 cases between 1998 and 1999 to 891 in 1999 to 2000. But the most dramatic drop off in disease came in second year after implementation when catch-up vaccination was recommended for children 1 to 9 years old.

By December 2001, with the aid of a national birth registry that follows children and compiles vaccination data, coverage with the vaccine reached 85% to 90%. These figures were on par with other regularly administered vaccines. As a result of the expanded coverage, there were only 410 cases in 2001.

There has even been evidence of herd immunity, Miller said. Group C meningitis has dropped off 67% among unvaccinated individuals and there has been a significant drop off in all age groups regardless of vaccination.

The interesting point about the degree of herd immunity, said Miller, is that it closely mirrors a 66% reduction in meningococcal carriage among 15-17-year-olds as reported by Martin Maiden, MD, and colleagues at Oxford University.

There have been 500 cases of meningitis due to group C N. meningitides in the two years since implementation of the vaccine, but only 57 among recipients of vaccine. However, only 36 of those were considered true vaccine failures; the remaining 21 either received an incomplete series of vaccine or had an onset of disease within 10 days of vaccination.

It takes about 10 days for the immune system to generate enough antibodies to protect against N. meningitides, said Miller.

For more information:

• Miller E. Meningococcal vaccines in the United Kingdom. Session 5: Vaccines. Presented at the 40th Annual Meeting of the Infectious Diseases Society of America. Oct. 24-27, 2002. Chicago.