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Novel Meningococcal Serogroup B Vaccine is Immunogenic

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Vaccine Is 'Major Step Forward'

In the last 10 years, introducing meningococcal conjugate vaccines has substantially reduced meningococcal disease. "Monovalent serogroup C vaccines have virtually eliminated serogroup C disease from the United Kingdom and other countries, and serogroup A, C, W, and Y vaccines have reduced disease among adolescents in the United States. These accomplishments have been dampened by the lack of effective serogroup B meningococcal vaccines. Serogroup B meningococcal disease causes substantial morbidity and mortality globally, especially in young infants," said Dr. Amanda C. Cohn and Dr. Nancy E. Messonnier.

"Serogroup B disease can be devastating," they emphasized. Five to ten percent of children with the disease die, and another 10%-20% may suffer hearing loss, limb loss, and neurologic deficits. Incidence of serogroup B disease is lower in the United States than in other countries, at 0.16 per 100,000 population but 3.08 per 100,000 population among infants younger than 1 year. Incidence of serogroup B disease in some of the countries in Europe, including the United Kingdom, is about ten times higher than in the United States.

"The report by Gossger and colleagues represents a major step forward in developing a broadly protective serogroup B vaccine that is safe and immunogenic in young infants," Dr. Cohn and Dr. Messonnier said. In fact, "studies evaluating antigen expression using isolates collected from surveillance suggest that 4CMenB vaccine could be protective against approximately 76% of strains circulating in Europe."

"Although the overall safety profile of the 4CMenB vaccine was similar to that of other routine infant vaccines, the rates of fever were higher. Six children who received 4CMenB vaccine (about 0.4%) were hospitalized for fever following 4CMenB vaccine, and one child experienced a febrile seizure," they noted. The high rates of fever are not surprising, based on previous data. "However, the high fever rates may cause some additional strain on the health system, including additional ambulatory visits and hospitalizations, and may dampen parental acceptance. The fever profile will likely be more acceptable in countries with a higher burden of serogroup B disease," they said.

"Booster doses may be required to sustain protection but may not confer the same degree of immunologic memory as conjugate vaccines. Countries will have to weigh the benefits of serogroup B vaccination against the costs of adding vaccines to the infant schedule. However, the anticipated licensure of this vaccine in Europe and other countries means that for the first time vaccines to prevent all five of the serogroups that cause most meningococcal disease worldwide will be available," Dr. Cohn and Messonnier concluded.

Dr. Cohn and Dr. Messonnier are at the National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta. Their comments are drawn from an editorial accompanying Dr. Gossger’s article (JAMA 2012;307:614-5). Dr. Cohn and Dr. Messonnier said they had no relevant financial disclosures.


 

FROM JAMA

An investigational recombinant vaccine against meningococcal serogroup B was immunogenic when given along with other vaccines in a study of more than 1,800 healthy infants.

The vaccine "was immunogenic, generally well tolerated, and showed minimal interference with routine vaccines in the first year of life. The flexibility in schedule allows it to be incorporated into a range of country-specific immunization schedules and for primary immunization to be completed in early infancy," said Dr. Nicoletta Gossger of Oxford Vaccine Group, University of Oxford, England, and her associates (JAMA 2012;307:573-82).

Currently available capsular polysaccharide-based vaccines protect against Neisseria meningitidis serogroups C, W-135, and Y but not B, because its capsular polysaccharide is poorly immunogenic in humans. Novartis Vaccines and Diagnostics developed a multicomponent serogroup B meningococcal vaccine (4CMenB) by combining novel antigens with outer membrane vesicles (OMV). Small studies in infants demonstrated immunogenicity of 4CMenB against reference strains (Clin. Infect. Dis. 2010;51:1127-37; Pediatr. Infect. Dis J. 2010;29:e71-9).

In the current phase IIb, open-label, parallel group, randomized controlled trial funded by the company, Dr. Gossger and her associates assessed the immunogenicity and reactogenicity of 4CMenB in 1,885 healthy, full-term 2-month-old infants from 60 centers in six European countries. The infants were randomized to one of three primary 4CMenB schedules: ages 2, 4, and 6 months, together with routine infant vaccines (concomitant); 2, 4, and 6 months, with routine vaccines given separately at 3, 5, and 7 months (intercalated); and 2, 3, and 4 months, concomitantly with routine infant vaccines (accelerated).

A control group received the diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b conjugate vaccine (Infanrix hexa) and the 7-valent pneumococcal conjugate vaccine (Prevnar) only at 2, 3, and 4 months. All immunization time points used in the study were chosen to reflect schedules currently used in different countries, Dr. Gossger and her associates noted.

Median age of the infants at enrollment was 68.7 days for all groups, 48%-53% of each group was boys, and 93% of all participants were white. Human complement serum bactericidal activity (hSBA) was assessed against three MenB strains specific for vaccine antigens. After immunization with 4CMenB and routine vaccines together at either 2, 4, and 6 months or 2, 3, and 4 months, 99% or more of participants had hSBA titers of 1:5 or greater (considered protective) for two of the strains (44/76-SL and 5/99) in the modified intention-to-treat immunogenicity analysis, which included 1,636 of the entire cohort.

For strain NZ98/254, which was chosen to determine the immunogenicity of the OMV, the percentages were 79% following the concomitant schedule, 86% for the intercalated schedule, and 82% following the accelerated schedule. Immune responses to all three strains met the predefined sufficiency criteria, the investigators reported.

Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. This is "unlikely to be of clinical significance," based on experience with other vaccines, Dr. Gossger and her associates commented.

During the study, less than 1% of the infants had severe erythema, swelling, or induration at the vaccination sites. Nonetheless, 12% to 16% in the concomitant and accelerated groups, respectively, had severe local pain after a dose of 4CMenB, compared with 1% to 3% after doses of DTaP-HBV-IPV/Hib or PCV7 in the control group.

Fever after any vaccination was reported in 80% the concomitant group and 76% in the accelerated group, compared with 51% in the control group and 71% in the intercalated group. For the intercalated group, there were twice as many immunization days, and thus there was more opportunity for fever to occur, they noted.

There were 166 serious adverse events reported in 158 infants, 63 (10%) in the concomitant group, 57 (9%) in the intercalated group, 19 (6%) in the accelerated group, and 19 (6%) in the control group. Of these adverse events, 20 (9 concomitant, 7 intercalated, 3 accelerated, and 1 control) were considered to be possibly related to 4CMenB or routine vaccinations.

"If licensed, the decisions regarding vaccine introduction will require detailed assessment of potential vaccine coverage at a regional level and monitoring after implementation to determine the accuracy of such predictions. Nevertheless, this vaccine could potentially provide improved protection for infants against meningococcal disease beyond the protection provided by currently licensed vaccines," Dr. Gossger and her associates said.

This study was funded by Novartis Vaccines and Diagnostics. Dr. Gossger reported no relevant financial disclosures. Several of the other study authors reported financial relationships with Novartis and other vaccine manufacturers and noncommercial funding bodies.

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