The first, documented one hundred years of cerebrospinal meningitis, during which the clinical course and worldwide occurrence of diseases were vividly described, was dominated by attempts at symptomatic and “alexipharmic”—antidote—therapy. That approach did little to alter the natural course and invariably fatal conclusion to this devastating disease. By the time that the clinical entity—now understood to be meningococcal meningitis—entered its second century, the body of knowledge in the sister sciences of microbiology and immunology had evolved to such a degree that it could support rigorous laboratory and clinical investigations of infectious diseases. This led to research—initially and largely carried out in the Institutes of the great cities of Europe—Paris, Vienna, and Berlin—but later advanced in New York, resulting in the first effective therapy for meningococcal disease. By 1907, the mortality rate would drop from seventy-five percent to thirty percent; physicians and scientists around the world felt as if they now had some measure of control against the infection.

Beginning in the 1930s with the discovery of the first, specific antibacterial drugs and continuing on for the next few decades, these “miracle” cures—antibiotics—further reduced the death rate of meningococcal disease, down to ten percent. In fact, antibacterial drugs were capable of preventing the disease in the first place if given before the initial signs or symptoms. Physicians became complacent; there was a sense that infectious diseases—up until that time among the most common and gravest threats to life and limb—could be forever vanquished as a cause for concern. However, within just a few years of the widespread use of these treatments, it had become clear that they were not the panacea initially envisioned.

With every new antibacterial drug introduced—and there were many during the mid-twentieth century—bacterial pathogens demonstrated new ways to rapidly become resistant to their beneficial effects. Outbreaks of antibiotic-resistant meningococcal meningitis occurred with increasing frequency during that time, most notably not only around military recruit camps but also in civilian populations around the world. As America prepared for war once again in the 1960s, it became clear that vaccines to prevent disease were the best hope for the eventual control of meningococcal meningitis. The invention of the first, effective polysaccharide vaccine against these germs demonstrated the path to this goal; the evolution of meningococcal vaccines over the past four decades has illuminated it.

After two centuries of epidemic meningococcal meningitis, there are now multiple, effective vaccine solutions, yet several residual, vexing problems regarding this disease remain unresolved. A polysaccharide vaccine that combines preparations of the capsules from four of the most common serogroups—a “quadrivalent” vaccine—has been used since the early 1980s. This first-generation vaccine combines polysaccharides from the four types of meningococci that are most commonly responsible for sporadic and epidemic disease—groups A and C, and two other groups found in various parts of the world—Y and W-135. It has been used largely in developed countries for prevention of disease in those at risk such as military recruits, college students living in dormitories, patients with deficiencies of their immune systems, or travelers to areas experiencing meningitis epidemics. The vaccine is not effective and therefore not recommended for use in children below the age of two years, as we have seen previously, although children as young as three months of age may demonstrate a short-term benefit of the vaccine, which makes it potentially useful in temporarily containing outbreaks.

The most commonly occurring meningococcal serogroups in the Americas and Europe are B, C, and increasingly, Y.¹ Group B, not included in any of the currently available vaccines, now causes a majority of disease in many parts of the world; to some extent, it has filled in and replaced other groups that are covered in the vaccine. Group A meningococci—now rarely seen in the developed world—are the major causes of recurring, devastating epidemics in Africa, China, and elsewhere in the developing world. Other serogroups such as C, W-135, and the relatively uncommon, group X, also contribute—albeit to much lesser degrees—to the meningitis problem there.

Because of the poor activity of polysaccharide vaccines in very young children—a major shortcoming that was successfully dealt with by linking polysaccharides to protein carriers—“conjugate” vaccines for meningococcal disease first became available for use in the late 1990s. The deployment of a group C meningococcal conjugate vaccine, comprising polysaccharide linked to either tetanus or diphtheria proteins, among preschool and school-aged children in the UK in 1999 proved highly effective, reducing meningitis cases and deaths by more than ninety percent. The vaccine even resulted in substantially lower numbers of meningococcal carriers among people who were not vaccinated—“herd” immunity. Therefore, the population in general benefitted from fewer meningococci circulating in the environment and the lower numbers of individuals with meningitis who could potentially transmit infection.²

A quadrivalent conjugate vaccine—containing the same meningococcal groups as in the older, first-generation quadrivalent vaccine but now linked to diphtheria toxoid—was licensed in the U.S. in 2005.³ Based on studies comparing its ability to provoke potentially protective antibody responses with those of the older polysaccharide vaccine, the meningococcal conjugate vaccine has been ­recommended as a routine immunization for adolescents and as an optional one for all children and adults—up to age 55—at increased risk of meningococcal disease. This particular conjugate vaccine has relatively poor activity in infants, prompting expanded development of more promising conjugates in the future for this population of potential meningitis victims.

Thus, the fundamental tools—conjugate vaccines against multiple serogroups—appear to be in place to embark on the final push towards prevention and control of meningococcal disease. But there remain significant impediments to realizing this ultimate goal. A major cause of worldwide disease—group B meningococcus—currently eludes a vaccine solution, for the reasons we have previously seen; in the African “meningitis belt,” frequent, cyclic, and sometimes massive, recurrent epidemics of meningococcal disease continue to devastate the overwhelmingly young population there. How will these problems be addressed? Which direction will future control take?

The approach to each of these two dilemmas currently hindering the prevention and control of meningococcal disease around the world has been distinct. Addressing the problem of group B meningococcal meningitis, by necessity, has required innovative strategies derived from the biology of the organism—in some cases using molecular-based methods that were not even in the realm of possibility just a decade ago. Here, the issue is one of designing a vaccine that can induce protective immunity directed against a germ that appears to the human immune system—from the outside at least—like part of its own human host. Conversely, the problem of epidemic meningococcal meningitis in sub-Saharan Africa may be amenable to more traditional vaccine approaches, using meningococcal polysaccharides conjugated to protein carriers. The issues here are not the vaccines per se, but their cost, the logistics and politics of their deployment, and the organizational infrastructure needed to bring them to the groups who need them the most in these developing parts of the world.

Group B meningococci continue to pose problems for vaccinologists. As we have seen, despite the fact that the core of these organisms is surrounded by a capsular polysaccharide—as is the case with other meningococcal serogroups—their polysaccharide coat does not engender protective antibody responses when formulated into a vaccine. Instead, the human immune system turns its attention elsewhere—“tolerates” it—because it looks too much like parts of its “self,” and the immune system is genetically programmed not to attack its own cells and tissues. With a polysaccharide type of vaccine out of contention, researchers have looked for other targets within the bacterium against which to direct immune responses.

The outer membrane of the group B meningococcus—the layer that separates the interior of the bacterium from the outside world—contains a number of different molecules that assist the germ in its efforts to evade the human immune system. Infectious diseases frequently result from such a chess game; a microbe struggles to survive in the hostile environment of its host, and in order to do this, it generally employs multiple strategies to avoid getting caught up in the body’s defenses. The group B meningococcus is no stranger to intrigue.