A Multivalent Conjugate Vaccine for Prevention of Meningococcal Disease in Infants

Major progress has been made in the development of meningococcal vaccines in the past few years. Monovalent serogroup C conjugate vaccines, shown to be immunogenic and effective in infants, have dramatically decreased the incidence of serogroup C disease in the countries in which they have been used.^{1 - 4} This reduction has occurred among those immunized and, through a decrease in pharyngeal carriage of serogroup C Neisseria meningitidis, also among the unimmunized population.^{5 - 6} These vaccines do not cover serogroup Y strains, an important cause of meningococcal disease across all age groups in the United States, including infants, and are not licensed in the United States. A new tetravalent (serogroups A, C, W-135, and Y) conjugate vaccine licensed for 2- to 55-year-olds is now recommended for all US adolescents, as well as other high-risk groups.⁷ This recommendation was based on the fact that US adolescents were found to have both a relatively high incidence of meningococcal disease and a high case fatality rate.^{7 - 8}

Unlike monovalent serogroup C vaccines, the currently licensed tetravalent conjugate vaccine was judged to be insufficiently immunogenic in infants, the group with the highest risk of meningococcal disease.⁹ An analysis conducted by Lingappa et al¹⁰ indicated that a combined approach of immunizing infants and adolescents and college students would have the largest effect in terms of number of cases and deaths prevented. It is clear that the current focus on adolescents in the United States is an interim measure; a multivalent vaccine for infants is also needed.¹¹

In this issue of JAMA, the report by Snape and colleagues¹² represents a substantial advance in the vaccine prevention of meningococcal disease because it provides evidence for a well-tolerated and immunogenic tetravalent (serogroups A, C, W-135, and Y) conjugate vaccine for infants. The study vaccine uses CRM-₁₉₇, a nontoxic mutant of diphtheria toxin, as the carrier protein and aluminum phosphate as an adjuvant. In this phase 2, open-label, randomized study conducted in 421 healthy infants in the United Kingdom and Canada, the authors evaluated two 3-dose primary schedules (1 dose each at 2, 3, and 4 or 2, 4, and 6 months of age) and a 2-dose schedule (2 and 4 months) given along with the other vaccines in the routine immunization schedule of the respective countries. An additional group received the serogroup C conjugate vaccine at 2 and 4 months of age. At 12 months of age, some children received a booster dose of the study vaccine, some received a reduced dose of tetravalent polysaccharide vaccine as a probe for immunologic memory, and some received no additional meningococcal vaccine. The strengths of the study include assessments of multiple immunization schedules, a booster dose at 12 months of age, and immunologic memory.

The primary objective of this study was to determine the proportion of children receiving 1 of the 3 primary dose schedules who had a human complement serum bactericidal antibody (hSBA) titer of 1:4 or greater against each of the meningococcal serogroups included in the vaccine 1 month after the primary series. In general, an hSBA titer of 1:4 or greater is considered to be protective, although there is evidence that this assay underestimates protective immunity. A key finding was that at least 92% of infants who received the 2-, 3-, 4-month schedule had an hSBA titer of 1:4 or greater to all 4 serogroups. For the 2-, 4-, 6-month schedule, similar results were obtained for serogroups C, W-135, and Y, but the proportion of infants with an hSBA titer of at least 1:4 against serogroup A was lower at 81%.

In the 2-, 4-month primary series groups, at least 84% had protective antibody levels to 3 of the 4 serogroups, with 60% to 66% of infants having a protective titer against serogroup A. Following a booster dose at 12 months, at least 95% of infants developed a protective antibody level to 3 of the 4 serogroups, and 84% for serogroup A. The results for study participants who received immune challenge with a reduced dose of plain polysaccharide vaccine at 12 months, when compared with historical controls, suggest that the study vaccines induced immunologic memory, a key property of conjugate vaccines. Administration of the study vaccine did not appear to adversely affect the immunogenicity of the concomitantly given pediatric vaccines. Moreover, reactogenicity was similar to what would be expected for a conjugate vaccine and, among children who received 2 doses of the study vaccine, was comparable with what was observed for children who received 2 doses of serogroup C conjugate vaccine.

What is the optimal immunization schedule among those studied? For all schedules, a substantial decline of hSBA geometric mean titers (GMTs) was seen for all serogroups by 12 months of age. This is analogous with what was seen for serogroup C conjugate vaccines, for which both a decline in antibody levels and evidence for lack of clinical protection were observed in infants who did not receive a booster dose after a 3-dose primary series.¹ There is substantial evidence that antibody persistence is more important for clinical protection than immunologic memory responses.^{1 ,13} Therefore, similar to serogroup C conjugate vaccines, a booster dose at 1 year of age will be required for sustained protection.

Although the authors suggest that a 2-, 4-, 12-month schedule would be preferable to the 2-, 4-, 6-, 12-month schedule for developed countries without a routine 6-month visit, the latter schedule is compatible with the US pediatric immunization schedule. In addition, the hSBA GMTs were higher after the 12-month booster dose with the 2-, 3-, 4-month primary schedule than with the 2-, 4-month primary schedule, suggesting that a 3-dose primary schedule might have a longer duration of protection than a 2-dose primary schedule. However, the study did not include the immunogenicity of a 2-, 4-, 6-month primary schedule followed by a booster dose of the study vaccine at 12 months, which would have been useful information for the United States. Nevertheless, taking all of the study results together, it would be expected that this schedule would be highly immunogenic, but this issue requires further study.

There are other unanswered questions about the study vaccine that need to be addressed in additional investigations, including more complete assessments of the potential interaction between the vaccine and the heptavalent pneumococcal conjugate vaccine, which also uses CRM-₁₉₇ as the protein carrier, and vaccine safety.

Assuming that the vaccine eventually becomes licensed, additional questions will likely be addressed post-licensure. The duration of immunity is an important issue to determine whether additional doses will need to be given between a childhood series and adolescence. Whether the lower hSBA responses for serogroup A are clinically relevant is not clear. The clinical significance of the lower serogroup C hSBA GMTs for the study vaccine than for serogroup C conjugate vaccine is also not clear. However, this is of potential relevance if this results in less sustained protective antibody levels and therefore shorter duration of clinical protection. These issues will need to be assessed using a combination of antibody persistence studies and meningococcal disease surveillance.

Postmarketing surveillance will be required to identify adverse events, if any, that are not detected before licensure. It is not known whether this new vaccine prevents pharyngeal carriage, a major public health benefit that has been seen with currently used conjugate vaccines, including Haemophilus influenzae type b, heptavalent pneumococcal, and serogroup C meningococcal vaccines. Given that the study vaccine behaves immunologically like a conjugate vaccine, it would be expected to reduce the acquisition of pharyngeal carriage of N meningitidis and therefore prevent disease in the unimmunized population. In the United Kingdom, the herd immunity effect with the serogroup C conjugate vaccines was demonstrated post-licensure through a large pharyngeal carriage study in adolescents and public health surveillance to determine the incidence of meningococcal disease in those who had and had not been immunized.^{5 - 6} Carriage studies in infants would be difficult, however, because of low meningococcal carriage rates in this population.

The United States, which experienced the dramatic emergence of serogroup Y meningococcal disease during the 1990s and also has some serogroup W-135 disease,¹⁴ most likely will benefit from the use of this vaccine in infants. Serogroup Y strains, which accounted for only about 2% of meningococcal disease cases in the United States in the late 1980s, dramatically increased in incidence and, by the mid-1990s, accounted for around a third of all cases.^{14 - 15} Use of the study vaccine in infants would complement the current US recommendation for universal immunization of adolescents.¹⁰ Other countries, such as Canada and South Africa, also have serogroup Y disease.^{16 - 18}

In many parts of the world, meningococcal disease is caused mostly by serogroup B and C strains, raising the question about the value of an A, C, W-135, and Y conjugate vaccine over and above the successful monovalent C conjugate vaccines. Cost aside, the optimal approach to vaccine prevention of meningococcal disease is to immunize against as many of the clinically relevant meningococcal serogroups as possible. This is because meningococcal serogroup distribution is unpredictable and, with immunization against a limited number of serogroups, there is the risk of emergence of strains of serogroups not included in the vaccine being used. As another example of the unpredictability of meningococcal serogroup distribution, a serogroup W-135 clone recently emerged as an unexpected cause of meningococcal epidemics in Saudi Arabia and subsequently in parts of sub-Saharan Africa.^{19 - 22} However, cost is an important issue for national immunization programs, and whether countries that currently have disease mainly caused by serogroup B and C strains will use the study vaccine remains to be seen. Regardless, given the fluid nature of meningococcal epidemiology, optimal immunization policy requires ongoing, high-quality surveillance to determine meningococcal disease incidence and serogroup distribution.

Even though this new vaccine represents substantial progress toward comprehensive worldwide prevention of meningococcal disease, much work remains ahead. There is still no broadly protective serogroup B vaccine. According to data from the Active Bacterial Core surveillance (ABCs) network, more than half of all meningococcal disease in US infants is caused by serogroup B strains; overall, this serogroup accounts for about a third of all disease in the United States.²³ In Europe, following the use of monovalent C conjugate in many countries, about 70% of all meningococcal disease is now caused by this serogroup,²⁴ a figure that approaches 90% in the United Kingdom.²⁵ Although the development of a broadly protective serogroup B vaccine has been exceedingly difficult despite the use of various antigens, reverse vaccinology to identify relatively conserved, surface exposed, and immunogenic meningococcal outer membrane protein antigens appears to be a promising approach.^{26 - 27}

Progress is being made toward a safe, efficacious, and affordable serogroup A conjugate vaccine for sub-Saharan Africa,^{28 - 29} which still experiences devastating serogroup A epidemics.³⁰ However, the recent occurrence of a serogroup W-135 epidemic and serogroup X outbreaks raises questions about the long-term success of a monovalent vaccine approach for this region of the world with the highest incidence of meningococcal disease.^{19 - 22 ,31}

The study by Snape and colleagues¹² represents a major advance in the vaccine prevention of meningococcal disease. Taken together with other ongoing progress, the outlook for comprehensive global prevention of this devastating disease has never been better.