Original Article
Immunogenicity and Safety of a Meningococcal A Conjugate Vaccine in Africans
N Engl J Med 2011; 364:2293-2304June 16, 2011
- Abstract
Background
Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed.
Methods
We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A–specific enzyme-linked immunosorbent assay.
Results
In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported.
Conclusions
The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.)
Media in This Article
Figure 1
Randomization and Follow-up of Subjects in Study A.Figure 2
Randomization and Follow-up of Subjects in Study B.Article Activity
- Article
For more than a century, major meningococcal meningitis epidemics have occurred every 10 to 12 years in what is known as the African meningitis belt, which stretches from Senegal to Ethiopia.1-3 The majority of these epidemics have been caused by group A Neisseria meningitidis, and incidence rates have been as high as 500 cases per 100,000 population, with most cases occurring in persons between 1 and 29 years of age.4,5 In 2009, more than 50,000 cases of group A meningococcal meningitis were reported in northern Nigeria.6 Because of the epidemic potential and high disease burden of group A meningococcal disease, controlling it is a public health priority in Africa.1-3,7
To address this problem, the World Health Organization (WHO) has emphasized case management and reactive emergency vaccination with polysaccharide vaccines.8,9 Although group A polysaccharide vaccine induces a solid antibody response in persons between 1 and 29 years of age and has been shown to be effective in African field trials,10-12 reactive vaccination campaigns are expensive and logistically difficult, and they have not eliminated meningococcal epidemics. In addition, the immunity induced by polysaccharide vaccines is short-lived and has little or no effect on carriage.13,14
In response to the need for more effective meningococcal vaccines in Africa, the Meningitis Vaccine Project (MVP), a partnership between the WHO and the Program for Appropriate Technology in Health (PATH), an international nonprofit organization, was established in 2001 with funding from the Bill and Melinda Gates Foundation. The goal of this partnership is to eliminate epidemics of group A meningitis through the development, testing, licensure, and introduction of a group A meningococcal conjugate vaccine that would be affordable in Africa.15 The new group A meningococcal conjugate vaccine, referred to here as PsA-TT, costs less than 50 cents per dose.15,16 After the completion of a phase 1 study involving healthy adults in India,17 two clinical studies were conducted to evaluate the safety and immunogenicity of a single dose of the PsA-TT vaccine as compared with that of a licensed vaccine with activity against meningococcal polysaccharide groups A, C, Y, and W135 in persons between 1 and 29 years of age. We report the results of both studies.
Methods
Study Design and Oversight
Studies A and B were double-blind, randomized, controlled, comparative trials designed to evaluate the immunogenicity and safety of a single injection of PsA-TT vaccine in healthy residents of the study areas; study A was also designed to evaluate the ability of the vaccine to induce immunologic memory. Study A was conducted among healthy children between 12 and 23 months of age at Centre pour le Développement des Vaccins in Bamako, Mali, and the Medical Research Council Laboratories in Basse, Gambia. Study B was conducted among healthy children and adults between 2 and 29 years of age in Mali, in Gambia, and at the Institut de Recherche pour le Développement in Niakhar, Senegal.
The participants in study A were 601 children, 12 to 23 months of age, who were randomly assigned in equal proportions to receive PsA-TT (MenAfriVac, Serum Institute of India); a reference vaccine, PsACWY (Mencevax ACWY, GlaxoSmithKline); or a control vaccine, Haemophilus influenzae type b conjugate Hib-TT, (Hiberix, GlaxoSmithKline). Ten months later, 589 of the participants underwent within-group randomization to receive a booster vaccination with a full dose of PsA-TT, one-fifth of a full dose of PsACWY, or a full dose of Hib-TT.18 In study B, participants between 2 and 29 years of age were recruited and evenly stratified according to age into three groups: 2 to 10 years, 11 to 17 years, and 18 to 29 years. They were then randomly assigned in a ratio of 2:1 to receive the PsA-TT vaccine or the PsACWY vaccine. Immunogenicity, reactogenicity, and short-term safety were assessed 4 weeks after both the primary and booster vaccinations were administered in study A and 4 weeks after the primary vaccination in study B. Immunogenicity was also evaluated 10 months after primary vaccination and 1 week after booster vaccination in study A. Only the staff members at the study sites who were responsible for preparing the vaccines were aware of group assignments; the subjects, other site staff members, investigators, laboratory personnel, and sponsors were unaware of group assignments throughout the study period.
The main criteria for exclusion were a history of vaccination against N. meningitidis within the preceding 6 years, known exposure to N. meningitidis within the preceding 3 months, allergy or known hypersensitivity after any vaccination, and a positive pregnancy test. (Further details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) Both studies were conducted in accordance with the study protocols (available at NEJM.org).
The trials were designed and conducted in accordance with the Good Clinical Practice Guidelines established by the International Conference on Harmonization and with the Declaration of Helsinki.
The Serum Institute of India provided all vaccines except the Mencevax vaccine used in study A, which was provided by GlaxoSmithKline; all vaccines were provided free of charge. All authors contributed to the writing of the study and participated in the decision to publish the manuscript. Each participating community provided permission to conduct the study, and written informed consent was obtained before enrollment from all subjects between 18 and 29 years of age and from all parents or guardians of subjects younger than 18 years of age. Information on approval of the study by various committees charged with monitoring research involving human subjects is provided in the Supplementary Appendix.
Vaccines
A reconstituted dose of PsA-TT vaccine (0.5 ml) contained 10 μg of group A polysaccharide conjugated to 10 to 33 μg of tetanus toxoid, 0.3 mg Al3+ in AlPO4 (aluminum phosphate) as adjuvant, TRIS buffer, 0.01% thimerosal, and 0.9% sodium chloride. A reconstituted dose of reference vaccine, PsACWY (0.5 ml), contained 50 μg of purified polysaccharide from each of the N. meningitidis groups A, C, Y, and W135; lactose; sodium chloride; and water for injection. A reconstituted dose of the control vaccine, Hib-TT (0.5 ml), used in study A contained 10 μg of the polyribosylribitol phosphate capsular polysaccharide of H. influenzae type b (Hib) conjugated to 20 to 40 μg of tetanus toxoid, lactose, and sodium chloride. Vaccines were injected intramuscularly in the right deltoid unless participants were younger than 2 years of age, in which case, the right thigh was injected; the one-fifth booster doses of the PsACWY vaccine were administered subcutaneously in the right deltoid.19
Immunologic Evaluation
Blood samples were obtained before vaccination and 4 weeks after the primary vaccination in study A and the single vaccination in study B. In study A, samples were also obtained before the booster vaccination (i.e., 10 months after primary vaccination), 1 week and 4 weeks after the booster vaccination. For each blood sample collected, a thick smear was examined for malaria. The immunogenicity of the PsA-TT vaccine and the group A component of the PsACWY vaccine was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing a group A–specific IgG enzyme-linked immunosorbent assay (ELISA). Measurement of SBA titers was performed at the Health Protection Agency, Manchester, United Kingdom,20 and the ELISA was performed at the Centers for Disease Control and Prevention (CDC), Atlanta, with the use of the standard reference serum CDC1992.21 The SBA reference strain was F8238, and titers were expressed as the reciprocal of the final serum dilution, resulting in a colony-count reduction of at least 50% after 60 minutes of incubation.
The primary end point for immunogenicity was seroconversion, defined as an SBA titer that was at least four times as high as that at baseline 28 days after immunization (e.g., baseline titers ≤4 required postimmunization titers ≥16). Other end points included a level of group A–specific IgG that was at least 4 times as high as that at baseline, an SBA titer of 8 or more and 128 or more,22 percentages of subjects with a group A–specific IgG concentration of 2 μg per milliliter or more, geometric mean titer, and geometric mean concentration.
Safety Evaluation
Subjects were observed for 30 minutes after vaccination to record and treat immediate reactions. Subjects were monitored for local and systemic postimmunization reactions during daily home visits for 4 days; adverse events were assessed for 1 month, and serious adverse events were assessed throughout the course of each study. Subjects (or their parents or guardians) were asked about tenderness and induration at the vaccination site; fever, vomiting, and diarrhea (for all subjects) as well as lethargy, irritability, and loss of appetite (for subjects between 1 and 10 years of age) and headache, fatigue, myalgia, and arthralgia (for subjects older than 10 years of age). Solicited reactions within 4 days were presumed to be vaccine-related. Assessment of causality in the case of unsolicited adverse events was performed by the study investigators at each site. A data and safety monitoring board was established for studies A and B.
Statistical Analysis
The primary objective of each study was to demonstrate that the PsA-TT vaccine was not inferior to the PsACYW vaccine, as determined by the achievement of an SBA titer that was at least four times as high as that at baseline (noninferiority margin for the titer increase, 0.10). The 95% confidence interval for the difference in the proportions of subjects with this response in the PsACWY and PsA-TT groups was calculated with the use of the Miettinen–Nurminen method.23 If the upper limit of the confidence interval was less than 0.10, the PsA-TT vaccine was considered to be noninferior to the PsACWY vaccine. The exact 95% confidence intervals for the binomial proportions were calculated for all applicable secondary end points in each vaccine group. The Cochran–Mantel–Haenszel test was used to compare the proportions between vaccine groups with adjustment for age in study B. Student's t-test and Fisher's exact test were used to compare the groups as appropriate. Reverse cumulative distribution curves were generated 4 weeks after primary immunization. All immunogenicity and safety analyses were conducted in the intention-to-treat population. Missing values were treated as missing at random. Data were analyzed with SAS software, version 9.1.3. Calculations of the sample size required for the noninferiority assessment were based on formulas derived by Farrington and Manning24 (see the Supplementary Appendix for details).
Results
Study Population
In study A, among the 669 subjects who underwent randomization, 601 (300 in Mali and 301 in the Gambia) received the primary vaccination between September 18 and November 6, 2006; and 589 received a booster vaccination 10 months later (Figure 1Figure 1
Randomization and Follow-up of Subjects in Study A.). In study B, among the 909 subjects who underwent randomization, 900 were vaccinated (300 subjects each in Mali, the Gambia, and Senegal) (Figure 2Figure 2Randomization and Follow-up of Subjects in Study B.). All vaccinated subjects were included in the analyses. Immunogenicity data on SBA titers were available for at least 93% of the subjects at each time point in both studies. Demographic and clinical characteristics of the subjects are summarized in the Supplementary Appendix.Immunogenicity
Immunogenicity was measured 4 weeks after primary vaccination. In study A, 96.0% of the subjects in the PsA-TT group (95% confidence interval [CI], 92.2 to 98.2) had SBA titers that were at least four times as high as those at baseline, as compared with 63.7% of subjects in the PsACWY group (95% CI, 56.5 to 70.5) and 35.6% of those in the Hib-TT group (95% CI, 28.8 to 42.7). In study B, 78.2% of the subjects in the PsA-TT group (95% CI, 74.7 to 81.5) and 46.2% of those in the PsACWY group (95% CI, 40.4 to 52.1) had titers that were at least four times as high as those at baseline. Similar changes in titer were noted across all age groups. On the basis of guidelines from the European Medicines Agency, the differences between the PsACWY and PsA-TT groups of –32.2 percentage points (95% CI, –39.6 to –25.0%) in study A and –32.0 percentage points (95% CI, –38.5% to –25.4%) in study B support a claim of superiority for the PsA-TT vaccine (P<0.001 for both comparisons).25
In studies A and B, the geometric mean SBA titers (Table 1Table 1
Immunogenicity Results in the Two Studies.) and the proportions of subjects with SBA titers of 128 or more after vaccination were significantly higher in the PsA-TT group than in the other vaccine groups (for details, see the Supplementary Appendix). Postimmunization levels of group A–specific IgG were significantly higher in the PsA-TT vaccine group than in the other vaccine groups in both studies and across all age groups. (See Table 1 for geometric mean concentrations according to vaccine type, and see the Supplementary Appendix for titers that were at least four times as high as those at baseline and for percentages of subjects with an IgG level of 2 μg per milliliter or more.) Reverse cumulative distribution curves for SBA titers according to study and age group are shown in Figure 3Figure 3
Reverse Cumulative Distribution Curves for Antibody Titers in Studies A and B, According to the Vaccine Group and the Age of the Subjects.; postimmunization results were consistently better with the PsA-TT vaccine.Persistence of Immunologic Response
Forty weeks after the primary vaccination in study A, the proportions of subjects who still had an increase by a factor of 4 or more in the SBA titer, as compared with the preimmunization titer, were 82.1% (95% CI, 75.9 to 87.2) in the PsA-TT group, 38.3% (95% CI, 31.4 to 45.5) in the PsACWY group, and 38.3% (95% CI, 31.5 to 45.6) in the Hib-TT group. The geometric mean SBA titers in the three groups were 1167.9 (95% CI, 873.7 to 1561.3), 47.2 (95% CI, 31.1 to 1.6), and 52.6 (95% CI, 34.1 to 81.0), respectively, and the proportions of subjects with SBA titers of 128 or more were 92.3% (95% CI, 87.6 to 95.6), 54.6% (95% CI, 47.3 to 61.7), and 54.1% (95% CI, 46.8 to 61.3), respectively.
A similar pattern characterized the between-group differences in geometric mean concentrations of group A–specific IgG, which were as follows: 1.0 μg per milliliter (95% CI, 0.9 to 1.3) in the PsA-TT group, 0.4 μg per milliliter (95% CI, 0.4 to 0.5) in the PsACWY group, and 0.1 μg per milliliter (95% CI, 0.1 to 0.2) in the Hib-TT group. Significant differences were also found between the PsA-TT vaccine group and the PsACWY and Hib-TT groups for the other end points based on group A–specific IgG values (a level that was at least four times as high as that at baseline and percentages of subjects with a concentration of 2 μg or more per milliliter); these data are provided in the Supplementary Appendix.
Immunologic Memory
To evaluate the ability of the study vaccines to induce immunologic memory, we measured geometric mean SBA titers and geometric mean concentrations of group A–specific IgG 7 days after the booster vaccination in study A. Among the subjects who received one fifth of the full dose of the PsACWY vaccine, geometric mean SBA titers were 8679.1 in the group primed with the PsA-TT, 2294.5 in the group primed with PsACWY, and 4418.6 in the group primed with Hib-TT. Among subjects who received PsA-TT as the booster dose, the geometric mean SBA titers were 21720.7 in the group primed with PsA-TT, 12214.2 in the group primed with PsACWY, and 14063.4 in the group primed with Hib-TT (Table 1). Serologic data recorded 28 days after the administration of boosters, summarized in Table 1, showed similar trends.
Safety
Postimmunization reactions and adverse events are shown in Table 2Table 2
Reactions and Adverse Events in the Two Studies.. No reactions occurred immediately after immunization. Rates of injection-site and systemic reactions during the first 4 days after immunization and rates of adverse events during the first 28 days after immunization were similar among vaccine groups. However, induration in study A and tenderness in study B were reported more frequently after primary vaccination in the PsA-TT group, whereas vomiting in study A and fatigue in study B were reported more frequently in the PsACWY group. Diarrhea (in study A), headache (in study B, among subjects 11 to 29 years of age), and fever (in study B, among subjects in all age groups — 2 to 29 years of age) were the most frequently reported systemic postimmunization reactions after primary vaccination. Local and systemic postimmunization reactions were transient and mild and resolved without sequelae.Commonly reported adverse events included malaria, respiratory infections, gastroenteritis, and conjunctivitis. All adverse events resolved without sequelae, and no vaccine-related adverse events were recorded. In study A, 16 serious adverse events were reported within 2 years after primary vaccination, and in study B, 5 serious adverse events in 5 subjects were recorded within 1 year. In study A, 5 of the 16 serious adverse events were fatal; no deaths were reported in study B. In both studies there were no significant differences among vaccine groups with respect to serious adverse events after vaccination (Table 2). For detailed data on solicited local and systemic reactions, adverse events, and serious adverse events, see the Supplementary Appendix.
Discussion
The level of SBA activity correlates with the degree of protection against meningococcal disease.26,27 An SBA titer at least four times as high as that at baseline is accepted as a criterion for seroconversion and has been used to support the licensing of the meningococcal conjugate vaccines Menactra (Sanofi Pasteur) and Menveo (Novartis) in the United States.28,29 This criterion can be particularly difficult to meet in a population with high baseline titers of antibodies against N. meningitidis. Among the subjects in study B who were older than 2 years of age, 75% had baseline functional antibody titers of 128 or higher. Nonetheless, we found that the criterion of an SBA titer at least four times as high as that at baseline worked well across all age groups in comparing the immunogenicity of the PsA-TT conjugate vaccine with that of the reference polysaccharide vaccine, PsACWY. The higher proportion of responses in the PsA-TT group than in the polysaccharide group indicated that the conjugate vaccine was superior.25
The maintenance of antibody levels over time is a key determinant of immunologic protection; when antibody levels decline, protection wanes, even if vaccinees are primed for the development of immunologic memory.30 The proportion of subjects with persistent antibody responses at 40 weeks was significantly higher with PsA-TT than with PsACWY, which suggests that recipients of the PsA-TT vaccine would have the benefit of a longer period of protection.
Conjugate vaccines, by recruiting T-helper cells, induce immunologic memory,31 whereas T-cell–independent polysaccharide vaccines are characterized by hyporesponsiveness after repeated administration.32 In study A, 7 and 28 days after a booster vaccination with PsACWY at one fifth of the full dose (10 μg), subjects who had been primed with the PsA-TT vaccine had significantly higher geometric mean SBA titers than those who had been primed with the PsACWY or Hib-TT vaccine. The decline in SBA from day 7 to day 28 may be attributable to the early rapid expansion of antibody-secreting cells, and thus increased antibody production, followed by a contraction or down-regulation of antibody-secreting cells as antigen becomes less available. Similar findings have been reported in other studies.33,34
A study conducted in the United States compared the effectiveness of a meningococcal quadrivalent polysaccharide–diphtheria conjugate vaccine with that of a variant of the PsACWY vaccine in children 2 to 10 years of age. Twenty-eight days after immunization, the geometric mean group A SBA titer was greater by a factor of only 0.9 as compared with the PsACWY vaccine (1700 [95% CI, 1512 to 1912], vs. 893 [95% CI, 791 to 1009] with the PsACWY vaccine),35 whereas in our two studies, titers were greater by factors of 16 (study A) and 3 (study B). Two other meningococcal quadrivalent conjugate vaccines have been shown to be immunogenic in toddlers and young children.36,37
Our data show that the new group A meningococcal conjugate vaccine, when tested in Africans between 1 and 29 years of age, had a safety profile similar to that of a licensed polysaccharide vaccine but elicited a significantly stronger and more persistent response from functional antibodies against group A meningococcus. The new vaccine also had the ability to induce immunologic memory. If widespread use of this new vaccine induces herd immunity, as was the case in the United Kingdom with a group C conjugate vaccine, it could potentially decrease epidemics of group A meningococcal infection in the African meningitis belt.
The views expressed in this article are those of the authors and do not necessarily represent the decisions, policies, or views of the WHO.
Supported by the Meningitis Vaccine Project (MVP) through a grant from the Bill and Melinda Gates Foundation.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Sow and Okoko contributed equally to this article.
We thank the study participants and their families and communities; the core teams at Centre pour le Développement des Vaccins in Mali (in particular, Dr. Mamoudou Kodio and Rokiatou Dembele), the Medical Research Council (MRC) in Basse, and the Institut de Recherche pour le Développement (IRD) in Niakhar; the MRC leadership and Dr. Jenny Mueller in Fajara, the MVP, Health Protection Agency (HPA), Centers for Disease Control and Prevention (CDC), and Serum Institute of India; the Malian, Gambian, and Senegalese Ministries of Health for their support; the WHO offices in Mali, Senegal, and Gambia for their advice and support throughout the study; the study monitors at the Agence Africaine de Recherche en Santé Humaine under the leadership of Dr. Véronique Mazarin-Diop; at DiagnoSearch Life Science (DLS), Drs. Manisha Ginde and Gandhali Paranjape for their support and diligence in the safety review; Poornima Savant, Prajakti Diwadkar, and their team for data management; Prathamesh Athavale and Reshma Sawant for their support of the statistical analyses; Drs. Musa Hassan-King and Katharina Hartmann for guidance at all stages of the research; Drs. M. Teresa Aguado, Marie-Paule Kieny, and Jean-Marie Okwo-Bele and Prof. Myron Levine for their support; the MVP advisory group (chaired by Prof. Francis Nkrumah) and the MVP Expert Panel (in particular, Prof. Brian Greenwood) for invaluable guidance; Drs. Suresh Jadhav, Subhash Kapre, Suresh Beri, Akshay Goel, and Karupothula Suresh from the Serum Institute of India; Dr. Jean-François Etard, Prof. Andrew J. Hall, and Mrs. Aissata Doumbia Diarra of the data and safety monitoring board; Julie Chatt-Soroka, Scott Johnson, Jeffery Martin (test operators), Doug Avery (quality manager), Dr. David Stephens, and Dr. Nancy Messonnier (advisory group) at the CDC; and Jamie Findlow, Daniel Holme, Helen Chadha, Lesley Mabey, Kelly Townsend, Danielle Thompson, and Charlotte Regan (test operators) at the HPA; Dr. Jean-Marie Préaud, Dr. Godwin Enwere, Muriel Socquet, Graciela Spizzamiglio, Kim Kertson, Gillian Stevens, Enricke Bouma, Marie-Françoise Makadi, Davegnee Servoz, Kathleen Tiffay, Colleen Ottosun, and Dr. Monique Berlier from MVP.
This article is dedicated to the memory of Dr. Brown J. Okoko, principal investigator of the study in Gambia, who died in September 2008.
Source Information
From the Centre pour le Développement des Vaccins, Bamako, Mali (S.O.S., M.T., F.C.H., F.D.); Medical Research Council Laboratories, Basse, Gambia (B.J.O., A.K.A., R.A.A., O.T.I.); Institut de Recherche pour le Développement, Dakar, Senegal (A.D., P.A., D.D.); the Meningitis Vaccine Project, Program for Appropriate Technology in Health, Ferney-Voltaire, France (S.V., J.C., L.M., Y.T., E.M., F.M.L.); Vaccine Evaluation Unit, Health Protection Agency North West, Manchester, United Kingdom (R.B., H.F.); Centers for Disease Control and Prevention, Atlanta (G.C., C.E., B.D.P.); DiagnoSearch Life Sciences, Mumbai (V.P.), and Serum Institute of India, Pune (P.S.K.) — both in India; and the Meningitis Vaccine Project, Initiative for Vaccine Research, World Health Organization, Geneva (M.-P.P.).
Address reprint requests to Dr. Preziosi at the Initiative for Vaccine Research, World Health Organization, 20 Ave. Appia, CH-1211 Geneva 27, Switzerland, or at preziosim@who.int.
Brown J. Okoko, M.D., M.P.H., is deceased.
- References
References
1
Lapeyssonnie L . La méningite cérébrospinale en Afrique. Bull World Health Organ 1963;28:Suppl:1-114
Medline2
Greenwood B . 100 Years of epidemic meningitis in West Africa -- has anything changed? Trop Med Int Health 2006;11:773-780
CrossRef | Web of Science | Medline3
Molesworth AM ,Thomson MC ,Connor SJ , et al. Where is the meningitis belt? Defining an area at risk of epidemic meningitis in Africa. Trans R Soc Trop Med Hyg 2002;96:242-249
CrossRef | Web of Science | Medline4
Campagne G ,Schuchat A ,Djibo S ,Ousseini A ,Cisse L ,Chippaux JP . Epidemiology of bacterial meningitis in Niamey, Niger, 1981-96. Bull World Health Organ 1999;77:499-508
Web of Science | Medline5
LaForce FM ,Ravenscroft N ,Djingarey M ,Viviani S . Epidemic meningitis due to Group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 2009;27:Suppl 2:B13-B19
CrossRef | Web of Science | Medline6
Meningococcal disease, African meningitis belt. Wkly Epidemiol Rec 2009;84:117-118
Medline7
Teyssou R ,Muros-Le Rouzic E . Meningitis epidemics in Africa: a brief overview. Vaccine 2007;25:Suppl 1:A3-A7
CrossRef | Web of Science | Medline8
Control of epidemic meningococcal disease: WHO practical guidelines (WHO/EMC/BAC/98.3). 2nd ed. Geneva: World Health Organization, 1998.
9
Enhanced surveillance epidemic meningococcal meningitis in Africa: a three-year experience. Wkly Epidemiol Rec 2005;80:313-320
Medline10
Wahdan MH ,Rizk F ,el-Akkad AM , et al. A controlled field trial of a serogroup A meningococcal polysaccharide vaccine. Bull World Health Organ 1973;48:667-673
Web of Science | Medline11
Erwa HH ,Haseeb MA ,Idris AA ,Lapeyssonnie L ,Sanborn WR ,Sippel JE . A serogroup A meningococcal polysaccharide vaccine: studies in the Sudan to combat cerebrospinal meningitis caused by Neisseria meningitidis group A. Bull World Health Organ 1973;49:301-305
Web of Science | Medline12
Saliou P ,Stoeckel P ,Lafaye A ,Rey JL ,Renaudet J . Controlled tests of anti-meningococcal polysaccharide A vaccine in the African Sahel area (Upper Volta and Mali). Dev Biol Stand 1978;41:97-108
Medline13
Hassan-King MK ,Wall RA ,Greenwood BM . Meningococcal carriage, meningococcal disease and vaccination. J Infect 1988;16:55-59
CrossRef | Web of Science | Medline14
Trotter CL ,Greenwood BM . Meningococcal carriage in the African meningitis belt. Lancet Infect Dis 2007;7:797-803
CrossRef | Web of Science | Medline15
LaForce FM ,Konde K ,Viviani S ,Preziosi MP . The Meningitis Vaccine Project. Vaccine 2007;25:Suppl 1:A97-A100
CrossRef | Web of Science | Medline16
Jodar L ,LaForce FM ,Ceccarini C ,Aguado T ,Granoff DM . Meningococcal conjugate vaccine for Africa: a model for development of new vaccines for the poorest countries. Lancet 2003;361:1902-1904
CrossRef | Web of Science | Medline17
Kshirsagar N ,Mur N ,Thatte U , et al. Safety, immunogenicity, and antibody persistence of a new meningococcal group A conjugate vaccine in healthy Indian adults. Vaccine 2007;25:Suppl 1:A101-A107
CrossRef | Web of Science | Medline18
Guerin PJ ,Naess LM ,Fogg C , et al. Immunogenicity of fractional doses of tetravalent A/C/Y/W135 meningococcal polysaccharide vaccine: results from a randomized non-inferiority controlled trial in Uganda. PLoS Negl Trop Dis 2008;2:e342-e342
CrossRef | Medline19
Ruben FL ,Froeschle JE ,Meschievitz C , et al. Choosing a route of administration for quadrivalent meningococcal polysaccharide vaccine: intramuscular versus subcutaneous. Clin Infect Dis 2001;32:170-172
CrossRef | Web of Science | Medline20
Maslanka SE ,Gheesling LL ,Libutti DE , et al. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. Clin Diagn Lab Immunol 1997;4:156-167
Medline21
Carlone GM ,Frasch CE ,Siber GR , et al. Multicenter comparison of levels of antibody to the Neisseria meningitidis group A capsular polysaccharide measured by using an enzyme-linked immunosorbent assay. J Clin Microbiol 1992;30:154-159
Web of Science | Medline22
Borrow R ,Balmer P ,Miller E . Meningococcal surrogates of protection -- serum bactericidal antibody activity. Vaccine 2005;23:2222-2227
CrossRef | Web of Science | Medline23
Miettinen O ,Nurminen M . Comparative analysis of two rates. Stat Med 1985;4:213-226
CrossRef | Web of Science | Medline24
Farrington CP ,Manning G . Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 1990;9:1447-1454
CrossRef | Web of Science | Medline25
Points to consider on switching between superiority and non-inferiority. London: EMEA, July 27, 2000. (CPMP/EWP/482/99.) (http://www.ema.europa.eu/pdfs/human/ewp/048299en.pdf.)
26
Frasch CE ,Borrow R ,Donnelly J . Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease. Vaccine 2009;27:Suppl 2:B112-B116
CrossRef | Web of Science | Medline27
Andrews N ,Borrow R ,Miller E . Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol 2003;10:780-786
Medline28
Food and Drug Administration. Menactra. Vaccines, blood, and biologics: approved products. August 24, 2009. (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm176044.htm.)
29
Idem. Menveo. Vaccines, blood, and biologics: approved products. March 17, 2011. (http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm201342.htm.)
30
Auckland C ,Gray S ,Borrow R , et al. Clinical and immunologic risk factors for meningococcal C conjugate vaccine failure in the United Kingdom. J Infect Dis 2006;194:1745-1752
CrossRef | Web of Science | Medline31
Richmond P ,Borrow R ,Goldblatt D , et al. Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers. J Infect Dis 2001;183:160-163
CrossRef | Web of Science | Medline32
Borrow R ,Joseph H ,Andrews N , et al. Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults. Vaccine 2000;19:1129-1132
CrossRef | Web of Science | Medline33
Keyserling H ,Papa T ,Koranyi K , et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med 2005;159:907-913
CrossRef | Web of Science | Medline34
Baxendale HE ,Keating SM ,Johnson M ,Southern J ,Miller E ,Goldblatt D . The early kinetics of circulating pneumococcal-specific memory B cells following pneumococcal conjugate and plain polysaccharide vaccines in the elderly. Vaccine 2010;28:4763-4770
CrossRef | Web of Science | Medline35
Pichichero M ,Casey J ,Blatter M , et al. Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children. Pediatr Infect Dis J 2005;24:57-62
CrossRef | Web of Science | Medline36
Black S ,Klein NP ,Shah J ,Bedell L ,Karsten A ,Dull PM . Immunogenicity and tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2-10 years of age. Vaccine 2010;28:657-663
CrossRef | Web of Science | Medline37
Knuf M ,Kieninger-Baum D ,Habermehl P , et al. A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children. Vaccine 2010;28:744-753
CrossRef | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Luiz Jacintho da Silva, Lisa DeTora, Claudius Malerczyk, Ziad A Memish. (2012) Emergence of Neisseria meningitidis W-135 in the context of other rare serogroups. Clinical Investigation 2:2, 177-188
CrossRef2
Claude-Roger Ouandaogo, Téné M. Yaméogo, Fabien V.K. Diomandé, Charles Sawadogo, Bassirou Ouédraogo, Rasmata Ouédraogo-Traoré, Lorenzo Pezzoli, Mamoudou H. Djingarey, Nehémie Mbakuliyemo, Patrick L.F. Zuber. (2012) Adverse events following immunization during mass vaccination campaigns at first introduction of a meningococcal A conjugate vaccine in Burkina Faso, 2010. Vaccine
CrossRef3
Marco AP Sáfadi, E David G McIntosh. (2011) Epidemiology and prevention of meningococcal disease: a critical appraisal of vaccine policies. Expert Review of Vaccines 10:12, 1717-1730
CrossRef4
Scott A. Halperin, Julie A. Bettinger, Brian Greenwood, Lee H. Harrison, Jane Jelfs, Shamez N. Ladhani, Peter McIntyre, Mary E. Ramsay, Marco A.P. Sáfadi. (2011) The changing and dynamic epidemiology of meningococcal disease. Vaccine
CrossRef5
Rino Rappuoli, Christian W. Mandl, Steven Black, Ennio De Gregorio. (2011) Vaccines for the twenty-first century society. Nature Reviews Immunology
CrossRef
