A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A.

Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) consists of (1 → 6)-2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, O-acetylated at position C3 or C4. Glycomimetics appear attractive to overcome the CPS intrinsic lability in physiological media, due to cleavage of the phosphodiester bridge, and to develop a stable vaccine with longer shelf life in liquid formulation. Here, we generate a series of non-acetylated carbaMenA oligomers which are proven more stable than the CPS. An octamer (DP8) inhibits the binding of a MenA specific bactericidal mAb and polyclonal serum to the CPS, and is selected for further in vivo testing. However, its CRM197 conjugate raises murine antibodies towards the non-acetylated CPS backbone, but not the natural acetylated form. Accordingly, random O-acetylation of the DP8 is performed, resulting in a structure (Ac-carbaMenA) showing improved inhibition of anti-MenA CPS antibody binding and, after conjugation to CRM197, eliciting anti-MenA protective murine antibodies, comparably to the vaccine benchmark.

An Update on Meningococcal Vaccination.

Neisseria meningitidis bacterial infection can cause severe life-threatening meningitis. Individuals who survive may be left with profound sequelae. In epidemic regions such as the meningitis belt of Africa, the case rate is drastically higher than in nonepidemic regions and is due to distinct outbreak serogroups. Two highly effective conjugate meningococcal vaccine against serogroups A, C, W and Y are licensed and indicated for prevention in childhood vaccination schedules and for travelers to outbreak regions. In the US, meningococcus serogroup B is the main cause of outbreaks, in areas with crowding such as college dorms. It has taken over 40 years to develop a meningitis type B vaccine and now there are 2 brands available for children and teens. All college-bound individuals should complete schedules of both conjugate ACWY serotypes and meningitis B vaccine series. This paper reviews details on who to vaccinate and how to use the currently available meningococcal meningitis vaccines.

Serogroup A meningococcal conjugate vaccines: building sustainable and equitable vaccine strategies.

INTRODUCTION: For well over 100 years, meningococcal disease due to serogroup A Neisseria meningitidis (MenA) has caused severe epidemics globally, especially in the meningitis belt of sub-Saharan Africa. AREAS COVERED: The article reviews the background and identification of MenA, the global and molecular epidemiology of MenA, and the outbreaks of MenA in the African meningitis belt. The implementation (2010) of an equitable MenA polysaccharide-protein conjugate vaccine (PsA-TT, MenAfriVac) and the strategy to control MenA in sub-Saharan Africa is described. The development of a novel multi-serogroup meningococcal conjugate vaccine (NmCV-5) that includes serogroup A is highlighted. The PubMed database (1996-2019) was searched for studies relating to MenA outbreaks, vaccine, and immunization strategies; and the Neisseria PubMLST database of 1755 MenA isolates (1915-2019) was reviewed. EXPERT OPINION: Using strategies from the successful MenAfriVac campaign, expanded collaborative partnerships were built to develop a novel, low-cost multivalent component meningococcal vaccine that includes MenA. This vaccine promises greater sustainability and is directed toward global control of meningococcal disease in the African meningitidis belt and beyond. The new WHO global roadmap addresses the continuing problem of bacterial meningitis, including meningococcal vaccine prevention, and provides a framework for further reducing the devastation of MenA.

Evaluation of the Impact of Meningococcal Serogroup A Conjugate Vaccine Introduction on Second-Year-of-Life Vaccination Coverage in Burkina Faso.

BACKGROUND: After successful meningococcal serogroup A conjugate vaccine (MACV) campaigns since 2010, Burkina Faso introduced MACV in March 2017 into the routine Expanded Programme for Immunization schedule at age 15-18 months, concomitantly with second-dose measles-containing vaccine (MCV2). We examined MCV2 coverage in pre- and post-MACV introduction cohorts to describe observed changes regionally and nationally. METHODS: A nationwide household cluster survey of children 18-41 months of age was conducted 1 year after MACV introduction. Coverage was assessed by verification of vaccination cards or recall. Two age groups were included to compare MCV2 coverage pre-MACV introduction (30-41 months) versus post-MACV introduction (18-26 months). RESULTS: In total, 15 925 households were surveyed; 7796 children were enrolled, including 3684 30-41 months of age and 3091 18-26 months of age. Vaccination documentation was observed for 86% of children. The MACV routine coverage was 58% (95% confidence interval [CI], 56%-61%) with variation by region (41%-76%). The MCV2 coverage was 62% (95% CI, 59%-65%) pre-MACV introduction and 67% (95% CI, 64%-69%) post-MACV introduction, an increase of 4.5% (95% CI, 1.3%-7.7%). Among children who received routine MACV and MCV2, 93% (95% CI, 91%-94%) received both at the same visit. Lack of caregiver awareness about the 15- to 18-month visit and vaccine unavailability were common reported barriers to vaccination. CONCLUSIONS: A small yet significant increase in national MCV2 coverage was observed 1 year post-MACV introduction. The MACV/MCV2 coadministration was common. Findings will help inform strategies to strengthen second-year-of-life immunization coverage, including to address the communication and vaccine availability barriers identified.

Meningococcal Meningitis Outbreaks in the African Meningitis Belt After Meningococcal Serogroup A Conjugate Vaccine Introduction, 2011-2017.

BACKGROUND: In 2010-2017, meningococcal serogroup A conjugate vaccine (MACV) was introduced in 21 African meningitis belt countries. Neisseria meningitidis A epidemics have been eliminated here; however, non-A serogroup epidemics continue. METHODS: We reviewed epidemiological and laboratory World Health Organization data after MACV introduction in 20 countries. Information from the International Coordinating Group documented reactive vaccination. RESULTS: In 2011-2017, 17 outbreaks were reported (31 786 suspected cases from 8 countries, 1-6 outbreaks/year). Outbreaks were of 18-14 542 cases in 113 districts (median 3 districts/outbreak). The most affected countries were Nigeria (17 375 cases) and Niger (9343 cases). Cumulative average attack rates per outbreak were 37-203 cases/100 000 population (median 112). Serogroup C accounted for 11 outbreaks and W for 6. The median proportion of laboratory confirmed cases was 20%. Reactive vaccination was conducted during 14 outbreaks (5.7 million people vaccinated, median response time 36 days). CONCLUSION: Outbreaks due to non-A serogroup meningococci continue to be a significant burden in this region. Until an affordable multivalent conjugate vaccine becomes available, the need for timely reactive vaccination and an emergency vaccine stockpile remains high. Countries must continue to strengthen detection, confirmation, and timeliness of outbreak control measures.

Status of the Rollout of the Meningococcal Serogroup A Conjugate Vaccine in African Meningitis Belt Countries in 2018.

BACKGROUND: A novel meningococcal serogroup A conjugate vaccine (MACV [MenAfriVac]) was developed as part of efforts to prevent frequent meningitis outbreaks in the African meningitis belt. The MACV was first used widely and with great success, beginning in December 2010, during initial deployment in Burkina Faso, Mali, and Niger. Since then, MACV rollout has continued in other countries in the meningitis belt through mass preventive campaigns and, more recently, introduction into routine childhood immunization programs associated with extended catch-up vaccinations. METHODS: We reviewed country reports on MACV campaigns and routine immunization data reported to the World Health Organization (WHO) Regional Office for Africa from 2010 to 2018, as well as country plans for MACV introduction into routine immunization programs. RESULTS: By the end of 2018, 304 894 726 persons in 22 of 26 meningitis belt countries had received MACV through mass preventive campaigns targeting individuals aged 1-29 years. Eight of these countries have introduced MACV into their national routine immunization programs, including 7 with catch-up vaccinations for birth cohorts born after the initial rollout. The Central African Republic introduced MACV into its routine immunization program immediately after the mass 1- to 29-year-old vaccinations in 2017 so no catch-up was needed. CONCLUSIONS: From 2010 to 2018, successful rollout of MACV has been recorded in 22 countries through mass preventive campaigns followed by introduction into routine immunization programs in 8 of these countries. Efforts continue to complete MACV introduction in the remaining meningitis belt countries to ensure long-term herd protection.

Vaccines and global health: In search of a sustainable model for vaccine development and delivery.

Most vaccines for diseases in low- and middle-income countries fail to be developed because of weak or absent market incentives. Conquering diseases such as tuberculosis, HIV, malaria, and Ebola, as well as illnesses caused by multidrug-resistant pathogens, requires considerable investment and a new sustainable model of vaccine development involving close collaborations between public and private sectors.

Antibody kinetics following vaccination with MenAfriVac: an analysis of serological data from randomised trials.

BACKGROUND: A meningococcal group A conjugate vaccine, PsA-TT (also known as MenAfriVac), was developed with the support of the Meningitis Vaccine Project. Around 280 million individuals aged 1-29 years have been immunised across the African meningitis belt. We analysed the kinetics of vaccine-induced antibody response and assessed the possible implications for duration of protection. METHODS: We obtained data from two longitudinal studies done in The Gambia, Mali, and Senegal of antibody responses in 193 children aged 12-23 months and 604 participants aged 2-29 years following MenAfriVac vaccination. Antibodies were measured using two methods: group A serum bactericidal antibody (SBA) assay and group A-specific IgG ELISA. Data on antibody responses were analysed using a mixed-effects statistical model accounting for the mean response and variation in patterns of antibody kinetics. Determinants of antibody duration were investigated using regression analysis. FINDINGS: In children age 12-23 months, the reduction in MenAfriVac-induced antibody levels assessed by SBA titres had two phases: with 97·0% (95% credible interval [CrI] 95·1-98·3) of the response being short lived and decaying within the first 6 months and the remainder being long lived and decaying with a half-life of 2690 days (95% CrI 1016-15 078). Antibody levels assessed by SBA titres in participants aged 2-29 years were more persistent, with 95·0% (85·7-98·1) of the response being short lived, and the long lived phase decaying with a half-life of 6007 days (95% CrI 2826-14 279). Greater pre-vaccination antibody levels were associated with greater immunogenicity following vaccination, as well as greater antibody persistence. Despite rapid antibody declines in the first phase, antibodies in the second phase persisted at SBA titres greater than 128. Although there is no strong evidence base for a correlate of protection against infection with Neisseria meningitidis serogroup A, we use an assumed SBA titre of 128 as a threshold of protection to predict that 20 years after vaccination with a single dose of MenAfriVac, vaccine efficacy will be 52% (29-73) in children vaccinated at age 12-23 months and 70% (60-79) in participants vaccinated at age 2-29 years. INTERPRETATION: Population-level immunity induced by routine vaccination with the Expanded Programme on Immunization is predicted to persist at levels sufficient to confer more than 50% protection over a 20-year time period. Further increases in population-level immunity could be obtained via mass campaigns or by delaying the age of vaccination through the Expanded Programme on Immunization. However, the benefits of such a strategy would need to be weighed against the risks of leaving young children unvaccinated for longer. FUNDING: Meningitis Vaccine Project and Institut Pasteur.

Antibody Persistence at the Population Level 5 Years After Mass Vaccination With Meningococcal Serogroup A Conjugate Vaccine (PsA-TT) in Burkina Faso: Need for a Booster Campaign?

Background: In Burkina Faso, serogroup A meningococcal (NmA) conjugate vaccine (PsA-TT, MenAfriVac) was introduced through a mass campaign in children and adults in December 2010. Similar to a serological survey in 2011, we followed population-level antibody persistence for 5 years after the campaign and estimated time of return to previously-published pre-vaccination levels. Methods: We conducted 2 cross-sectional surveys in 2013 and early 2016, including representative samples (N = 600) of the general population of Bobo-Dioulasso, Burkina Faso. Serum bactericidal antibody titers (rabbit complement) were measured against NmA reference strain F8236 (SBA-ref), NmA strain 3125 (SBA-3125), and NmA-specific immunoglobulin G (IgG) concentrations. Results: During the 2016 survey, in different age groups between 6 and 29 years, the relative changes in geometric means compared to 2011 values were greater among younger age groups. They were between -87% and -43% for SBA-ref; -99% and -78% for SBA-3125; and -89% and -63% for IgG. In linear extrapolation of age-specific geometric means from 2013 to 2016, among children aged 1-4 years at the time of the PsA-TT campaign, a return to pre-vaccination levels should be expected after 12, 8, and 6 years, respectively, according to SBA-ref, SBA-3125, and IgG. Among older individuals, complete return to baseline is expected at the earliest after 11 years (SBA-ref and SBA-3125) or 9 years (IgG). Conclusions: Based on SBA-3125, a booster campaign after 8 years would be required to sustain direct immune protection for children aged 1-4 years during the PsA-TT campaign. Antibodies persisted longer in older age groups.

Initial validation of a simulation model for estimating the impact of serogroup A Neisseria meningitidis vaccination in the African meningitis belt.

We previously developed a mathematical simulation of serogroup A Neisseria meningitidis (NmA) transmission in Burkina Faso, with the goal of forecasting the relative benefit of different vaccination programs. Here, we revisit key structural assumptions of the model by comparing how accurately the different assumptions reproduce observed NmA trends following vaccine introduction. A priori, we updated several of the model's parameters based on recently published studies. We simulated NmA disease under different assumptions about duration of vaccine-induced protection (including the possibility that vaccine-induced protection may last longer than natural immunity). We compared simulated and observed case counts from 2011-2017. We then used the best-fit model to forecast the impact of different vaccination strategies. Our updated model, with the assumption that vaccine-induced immunity lasts longer than immunity following NmA colonization, was able to reproduce observed trends in NmA disease. The updated model predicts that, following a mass campaign among persons 1-29 years of age, either routine immunization of 9 month-old children or periodic mini-campaigns among children 1-4 years of age will lead to sustained control of epidemic NmA in Burkina Faso. This validated model can help public health officials set policies for meningococcal vaccination in Africa.

Spontaneous point mutations in the capsule synthesis locus leading to structural and functional changes of the capsule in serogroup A meningococcal populations.

Whole genome sequencing analysis of 100 Neisseria meningitidis serogroup A isolates has revealed that the csaABCD-ctrABCD-ctrEF capsule polysaccharide synthesis locus represents a spontaneous point mutation hotspot. Structural and functional properties of the capsule of 11 carriage and two disease isolates with non-synonymous point mutations or stop codons in capsule synthesis genes were analyzed for their capsular polysaccharide expression, recognition by antibodies and sensitivity to bactericidal killing. Eight of eleven carriage isolates presenting capsule locus mutations expressed no or reduced amounts of capsule. One isolate with a stop codon in the O-acetyltransferase gene expressed non-O-acetylated polysaccharide, and was not recognized by anti-capsule antibodies. Capsule and O-acetylation deficient mutants were resistant to complement deposition and killing mediated by anti-capsular antibodies, but not by anti-lipopolysaccharide antibodies. Two capsule polymerase mutants, one carriage and one case isolate, showed capsule over-expression and increased resistance against bactericidal activity of both capsule- and lipopolysaccharide-specific antibodies. Meningococci have developed multiple strategies for changing capsule expression and structure, which is relevant both for colonization and virulence. Here we show that point mutations in the capsule synthesis genes substantially contribute to the repertoire of genetic mechanisms in natural populations leading to variability in capsule expression.

Impact of serogroup A meningococcal conjugate vaccine for Africa.

The introduction of a serogroup A meningococcal conjugate vaccine in the African meningitis belt has been a remarkable success. Meningitis due to the serogroup A meningococcus, previously responsible for most epidemics, has fallen by 99% in vaccinated countries. Success must, however, not distract from the continuing burden of meningitis in this region of Africa. The number of all meningitis epidemics at health district level has fallen by 60% following vaccination, but epidemics due to other meningococcal serogroups continue and may be increasing. The introduction of low cost multivalent conjugate vaccines must be given high public health priority.

Lessons from the Meningitis Vaccine Project.

From 2001 to 2017 the Meningitis Vaccine Project (MVP), a Gates Foundation funded partnership between PATH and the World Health Organization (WHO), successfully developed, tested, licensed, and introduced an affordable new Group A meningococcal conjugate vaccine, MenAfriVac, in sub-Saharan Africa. The vaccine was well received, and from 2010 to 2016, over 260 million Africans have received a dose of the vaccine in campaigns largely directed at 1­29-year olds. The public health impact has been dramatic with the elimination of Group A meningococcal infections wherever the vaccine has been used at public health scale. Over its 16-year life span, MVP faced many challenges, and lessons were learned that may be of interest to other groups seeking to develop vaccine products for resource-poor countries. We have chosen to highlight six elements that were keys to the success of the project: (a) country and African regional engagement during all phases of the project; (b) the evolution of the WHO/PATH partnership; (c) funding the introduction of MenAfriVac in meningitis belt countries; (d) regulatory challenges; (e) clinical trials in Africa and India; and (f ) the realities of vaccine development partnerships.

Developmental strategy for a new Group A meningococcal conjugate vaccine (MenAfriVacR).

Until recently, periodic Group A meningococcal meningitis outbreaks were a major public health problem in the sub-Saharan Africa. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, a Seattle-based NGO, and the Serum Institute of India Pvt Ltd (SIIPL) initiated discussions aimed at establishing a collaboration to develop a Group A meningococcal conjugate vaccine for this unmet medical need. Over the next 8 years the partnership made countless strategic decisions about product characteristics, raw materials, potential target populations, geographic prioritization and affordability of the vaccine to name a few. These decisions evolved into detailed plans for preclinical development, extensive field trials in Africa and India and a focused regulatory strategy specific for the Men A conjugate vaccine. Important characteristics of the process included, flexibility, transparency andeffective partnerships that included public agencies as well as private companies in Africa, Europe, the United States and India.

Successful African introduction of a new Group A meningococcal conjugate vaccine: Future challenges and next steps.

The introduction of a new Group A meningococcal conjugate vaccine, MenAfriVacR, has been a important public health success. Group A meningococcal meningitis has disappeared in all countries where the new Men A conjugate vaccine has been used at public health scale. However, continued control of Group A disease in sub-Saharan Africa will require that community immunity against Group A meningococci be maintained. Modeling studies have shown that unless herd immunity is maintained Group A meningococcal disease will return. To ensure that African populations remain protected birth cohorts must be protected with an EPI formulation of MenAfriVacR (5 mcg) given at 9 months with Measles 1. In addition, populations born after the initial 1-29 year old campaigns and consequently not yet immunized with the new Men A conjugate vaccine, will have to be immunized in country-specific catch-up campaigns. Countries with poor EPI coverage (Measles 1 coverage < 60%) will likely need quinquennial vaccination campaigns aimed at covering 1-4 year olds. Implementing these strategies is the only sure way of ensuring that Group A meningococcal meningitis epidemics will not recur. A second problem that requires urgent attention is the challenge of dealing with Non-A meningococcal meningitis epidemics in sub-Saharan Africa. Groups C, W and X meningococci are well-established circulating strains in sub-Saharan Africa and are responsible for yearly focal meningitis epidemics that vary in severity and remain unpredictable as to size and geographic distribution. For this reason, polyvalent meningococcal conjugate vaccines that are affordable and appropriate for the African context must be developed and introduced. These new meningococcal vaccines when combined with more affordable pneumococcal conjugate vaccines offer the promise of a meningitis-free Sub-Saharan Africa.

Evaluation of immunological responses to recombinant Porin A protein (rPoA) from native strains of Neisseria meningitidis serogroups A and B using OMV as an adjuvant in BALB/c mice.

Neisseria meningitidis is one of the main causes of sepsis and meningitis, which are two serious life-threatening diseases in both children and adolescents. Porin A (porA) from both serogroup A and B were cloned into the pET28a plasmid and expressed in E. coli BL21 (DE3). The protein was expressed in Escherichia coli BL21 (DE3) and confirmed by SDS-PAGE and Western blot analysis. BALB/c mice were subcutaneously injected three times with 25 µg of the recombinant PorA. Specific total IgG antibodies and isotypes were evaluated using ELISA assay. Opsonophagocytic assay (OPA) and Serum Bactericidal assay (SBA) were performed. Results showed that vaccinated mice exhibited higher levels of anti-Porin A (p < 0.05) with a predominant IgG1 response compared to the control group. Results from in vitro experiments indicated that N. meningitidis was opsonized with immunized-mice sera, and compared to non-immunized mice, immunized mice displayed significantly increased phagocytic uptake and effective intracellular killing. In this study, serogroup B N. meningitidis OMV of strain CSBPI G-245 and complete and incomplete Freund's adjuvant were used. Results demonstrated that Porin A could be a valuable target for the development of immunotherapeutic strategies against N. meningitidis.

Capsule switching of Neisseria meningitidis sequence type 7 serogroup A to serogroup X.

OBJECTIVES: The bacterial pathogen Neisseria meningitidis is able to escape the currently available capsule-based vaccines by undergoing capsule switching. In this study, we investigated whether capsule switching has occurred in a recently emerged sequence type (ST) 7 serogroup X isolate in China, for which currently no vaccine is available. METHODS: To identify capsule switching breakpoints, the capsule locus and flanking regions of the ST-7 serogroup X isolate and three endemic ST-7 serogroup A isolates were sequenced and compared. To obtain further insight into capsule switching frequency and length of DNA fragments involved, capsule switching assays were performed using genomic DNA containing combinations of antibiotic selection markers at various locations in the capsule locus and flanking regions. RESULTS: Sequence analyses showed that capsule switching has occurred and involved a 8450 bp serogroup X DNA fragment spanning the region from galE to ctrC. Capsule switching assays indicate that capsule switching occurs at a frequency of 6.3 × 10-6 per bacterium per µg of DNA and predominantly involved DNA fragments of about 8.1-9.6 kb in length. CONCLUSIONS: Our results show that capsule switching in N. meningitidis occurs at high frequency and involves recombination in the flanking regions of the capsule biosynthesis genes.

Immunogenicity of a Booster Dose of Quadrivalent Meningococcal Conjugate Vaccine in Previously Immunized HIV-Infected Children and Youth.

BACKGROUND: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection. METHODS: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer ≥1:128) or a ≥4-fold increase 1 week after the booster dose. Primary response was defined as either a ≥4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose. RESULTS: Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were ≥90% for all serogroups. No serious adverse events were encountered. CONCLUSIONS: A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination.

The immunogenicity and safety of a Hib-MenAC vaccine: a non-inferiority randomized, observer-blind trial in infants aged 3-5 months.

BACKGROUND: The objective of this study was to evaluate the immunogenicity and safety of the novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup A and C-tetanus toxoid conjugate vaccine (Hib-MenAC). METHODS: We conducted a non-inferiority, randomized, observer-blind, positive control clinical trial in 900 healthy infants aged between 3-5 months in Funing County, Jiangsu Province, China. Participants were randomly allocated, in a ratio of 2:1 (block = 6), to receive experimental combined Hib-MenAC vaccines co-administrated with placebo or the co-administration of licensed Hib vaccine and MenAC vaccine, according to a three-dose immunization schedule. The seroconversion of antibody titer against meningococcal serogroups A, C and Hib was the primary endpoint. RESULTS: The experimental vaccines was non-inferior to the licensed two control vaccines. Participants receiving experimental Hib-MenAC vaccines showed a seroconversion rate of 99.0%, 96.1% and 97.7% for rSBA-MenA, rSBA-MenC and anti-PRP antibodies, respectively. The Hib-MenAC vaccine did not result in an increase in adverse reaction, and no serious adverse event was judged to be related to the vaccination. CONCLUSIONS: The novel combined Hib-MenAC conjugate vaccine was safe and highly immunogenic in infants aged between 3 to 5 months.