Meningococcal vaccine in travelers

PURPOSE OF REVIEW: New vaccines to prevent meningococcal disease have been licensed in recent years. It is therefore timely to discuss current vaccine strategies pertinent to international travelers in relation to the changing epidemiology. RECENT FINDINGS: Serogroup W135 achieved epidemic status in Africa in 2002, and then largely disappeared over a short time period. The year 2006 saw a marked epidemic rise in meningitis attack rates across the meningitis belt in Africa. This rise was mainly due to a new serogroup A strain, indicating that a new meningitis epidemic wave is beginning in Africa. Epidemics are also spreading south of the meningitis belt, including the Greater Lakes Area (Burundi, Rwanda, Republic of Tanzania). The new quadrivalent conjugate meningococcal vaccine is now licensed in North America but not elsewhere. In most other industrialized countries, the serogroup C conjugate vaccine is licensed. Plain polysaccharide quadrivalent vaccines are available almost worldwide. SUMMARY: Quadrivalent meningococcal vaccination is a visa requirement for Hajj and Umrah pilgrims to Saudi Arabia. Travelers to the meningitis belt during the dry season should be advised to receive meningococcal vaccine that covers all four serogroups. This recommendation should be extended to the Greater Lake Area, because of recent epidemics. Vaccine choices depend on availability.     

Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity

BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.     

CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells

Neisseria meningitidis is one of the leading causes of bacterial meningitis and septicemia in children. Vaccines containing the purified polysaccharide capsule from the organism, a T cell-independent antigen, have been available for decades but do not appear to provide protection in infancy or immunologic memory as measured by antibody responses. By contrast, T cell-dependent serogroup C protein-polysaccharide conjugate vaccines protect against serogroup C meningococcal disease from infancy onward and prime for immunologic memory. We compared the magnitude and kinetics of plasma cell and memory B-cell responses to a meningococcal plain polysaccharide vaccine and a serogroup C glycoconjugate vaccine in adolescents previously primed with the conjugate vaccine. Plasma cell kinetics were similar for both vaccines, though the magnitude of the response was greater for the glycoconjugate. In contrast to the glycoconjugate vaccine, the plain polysaccharide vaccine did not induce a persistent immunoglobulin G (IgG) memory B-cell response. This is the first study to directly show that serogroup C meningococcal glycoconjugate vaccines induce persistent production of memory B cells and that plain polysaccharide vaccines do not, supporting the use of the conjugate vaccine for sustained population protection. Detection of peripheral blood memory B-cell responses after vaccination may be a useful signature of successful induction of immunologic memory during novel vaccine evaluation.     

Conjugate vaccine introduction in the African meningitis belt: meeting surveillance objectives

The epidemiology of bacterial meningitis will change with introduction of meningococcal and pneumococcal conjugate vaccines in the African meningitis belt. The principal objectives of surveillance are to evaluate the impact of vaccination, to detect and investigate epidemics and provide material for research. The capacity of existing surveillance activities in the meningitis belt to meet these objectives varies due to infrastructural and financial constraints. Impact assessment of conjugate vaccine against meningococcal serogroup A will be limited to comparing incidence trends from a few surveillance sites with data obtained before vaccine introduction and to comparing trends in the incidence of suspected cases or localised epidemics in most other settings. The timeliness of detection of epidemics and identification of epidemic meningococcal serogroups could be improved in most countries by analysing suspected case data in health centre level resolution and by investigating outbreaks with mobile teams. For research and impact assessment of pneumococcal conjugate vaccines, several surveillance sites covering at least 0.5 million inhabitants should be maintained which undertake exhaustive case finding and systematic laboratory confirmation of meningitis and pneumonia. Molecular diagnostics will facilitate surveillance in remote areas, but the available techniques should be evaluated for diagnostic performance in the field and long‐term sustainability.     

Influence of prior meningococcal C polysaccharide vaccination on the response and generation of memory after meningococcal C conjugate vaccination in young children.

To determine whether the immunological hyporesponsiveness induced by meningococcal AC polysaccharide (MACP) vaccines can be overcome by meningococcal C conjugate (MCC) vaccine in young children, serum bactericidal antibody (SBA) serogroup C-specific IgG and IgG avidity indices were measured in young children who received MACP vaccine, followed 7 months later by MCC vaccine, and their responses were compared with those in age-matched MACP-naive control children, who received a single dose of MCC vaccine. For children <1 year of age at MACP vaccination, the SBA geometric mean titer (GMT) after MCC vaccination was lower (P=.022) and proportions with SBA titers <8 (P=.0083) or <128 (P=.0091) were higher than those in the control children. For older children, there was no difference in the SBA GMTs between the study and control groups (P>.5) or in the proportion with SBA titers <8 (P=1.00) or <128 (P=.98). No increase in avidity occurred after MACP vaccination, whereas avidity increased significantly 1 month after MCC vaccination, with a further increase at 6 months, which indicates that the induction of immunological memory was not impaired.     

Immune response of premature infants to meningococcal serogroup C and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus influenzae type b conjugate vaccines.

To determine the immune response of premature infants to meningococcal serogroup C capsular polysaccharide (MCC) and combined diphtheria-tetanus toxoids-acellular pertussis-Haemophilus influenzae type b (DTaP-Hib) conjugate vaccines, 105 infants born at <32 weeks' gestation had Hib IgG geometric mean concentrations (GMCs) and MCC serum bactericidal antibody (SBA) geometric mean titers (GMTs) measured 1 month after the third immunization. Term infants served as control subjects. Premature infants had Hib GMCs of 0.27 microg/mL, with 21% achieving GMCs >1.0 microg/mL, compared with 0.81 microg/mL and 46% in term infants (P<.001 and P=.003, respectively). The MCC SBA GMT was 398, with 99% achieving an SBA > or =8, compared with 380 and 98% in term infants (P=.84 and P=1.0, respectively). Hib IgG was associated with age at third immunization (P<.001). When combined with the DTaP vaccine used in this study, the Hib GMC of premature infants was extremely low. The SBA GMT to MCC was similar to that of term infants.     

Advances with vaccination against Neisseria meningitidis

In the last decade, meningococcal serogroup C conjugate vaccination programs have been demonstrated to be hugely successful with a truly impressive public health impact. In sub‐Saharan Africa, with the implementation of an affordable serogroup A conjugate vaccine, it is hoped that a similar public health impact will be demonstrated. Challenges still remain in the quest to develop and implement broadly protective vaccines against serogroup B disease. New, broad coverage vaccines against serogroup B are for the first time becoming available although little is known about their antibody persistence, effectiveness or effect on nasopharyngeal carriage. Enhanced surveillance following any potential vaccine introduction against serogroup B needs to be thoroughly implemented. The future now holds a distinct possibility, globally, for substantially decreasing meningococcal disease, regardless of infecting serogroup.     

Clinical and immunologic risk factors for meningococcal C conjugate vaccine failure in the United Kingdom

BACKGROUND: The meningococcal serogroup C conjugate (MCC) vaccine was introduced into the United Kingdom with licensure based on immunogenicity data not efficacy data. METHODS: All subjects with laboratory-confirmed meningococcal serogroup C (MenC) disease from January 2000 to December 2003 in England and Wales were followed up. A vaccine failure was defined as a laboratory-confirmed case of MenC disease occurring > or =10 days after the subject's last scheduled dose of MCC vaccine. Total immunoglobulins, serum bactericidal antibody (SBA) titers, MCC anticapsular antibody levels, and avidity indices (AIs) were measured in acute and convalescent serum samples from subjects with vaccine failure and unvaccinated subjects with MenC disease. RESULTS: Of 465 subjects with confirmed MenC disease identified among those eligible for vaccination, information on vaccination history was obtained for 462 (99.4%); of these, 53 were subjects with vaccine failure. SBA titers in convalescent serum samples and AIs in acute serum samples were significantly higher in subjects with vaccine failure than in unvaccinated subjects, (6.1-fold higher for SBA titers [P=.03] and 3.2-fold higher for AIs [P=.001]). CONCLUSIONS: The antibody response in the subjects with vaccine failure was consistent with an anamnestic response, suggesting that MenC disease occurred despite the MCC vaccine priming for immune memory. Persistence of antibodies may be a more appropriate correlate of long-term protection for MCC vaccines than the ability to generate a booster response on exposure.     

Natural and vaccine-induced immunity and immunologic memory to Neisseria meningitidis serogroup C in young adults.

The immune response to polysaccharides and conjugate vaccines in adults is poorly understood. This study assessed meningococcal serogroup C responses after AC polysaccharide (MACP) and C conjugate (MCC) vaccine administration in young adults and explored immune memory by measuring antibody avidity. The geometric mean avidity indices (GMAIs) measured 1 month after MACP vaccination were relatively high and failed to increase significantly in the 6 months before and after a second dose of MACP/MCC. Although the GMAI of naive adults increased immediately following MCC vaccination to 215.7 (95% confidence interval, 181.0-257.1), a level similar to that seen after MACP vaccination, no further maturation in the subsequent 6 months was seen. Antibody induced by polysaccharide antigens in adults is already of relatively high avidity (compared with that in infants and toddlers) and fails to mature further, probably because both MACP and MCC predominantly stimulate memory B cells.     

Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination

The UK was the first place to introduce meningococcal serogroup C conjugate (MCC) vaccines. From November, 1999, all people younger than 18 years, about 14 million individuals, were offered MCC immunisation. The uptake rate was more than 70% by November, 2000. We compared the carriage of meningococci in isolates we obtained from 14,064 students aged 15-17 years during vaccination in 1999, with those from 16,583 students of the same age surveyed 1 year later. Carriage of serogroup C meningococci was reduced by 66% (p=0.004). Our results show that MCC vaccines protect against carriage of meningococci that express serogroup C polysaccharide capsules.     

Haemophilus influenzae type b conjugate vaccine use and effectiveness

Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children, including meningitis and pneumonia. The introduction of Hib conjugate vaccines into routine vaccination schedules has contributed to a substantial reduction in the burden of Hib-related disease in many developed countries. However, introduction of Hib conjugate vaccines in developing countries has progressed more slowly. We review the worldwide use and effectiveness of Hib conjugate vaccines. At present, 119 countries have programmes for routine Hib immunisation. WHO estimates that in the developed world 92% of the eligible population is vaccinated against Hib; however, average coverage is 42% in developing countries and only 8% in the poorest countries. Africa and southeast Asia have the lowest rates of Hib vaccine introduction. Vaccine costs and debate about the burden of disease are obstacles to the global use of Hib conjugate vaccine. Even with new funding support, there are many ongoing challenges and vaccine use remains suboptimal, particularly in developing countries.     

Conjugate vaccines--a breakthrough in vaccine development

The encapsulated bacteria Streptococcus pneumoniae (the pneumococcus), Neisseria meningitidis (the meningococcus) and Haemophilus influenzae type b (Hib) are the main causes of purulent meningitis, the peak incidence of which is seen in the first two years of life. The polysaccharide capsule of these bacteria is an essential virulence determinant, and antibodies to it are protective, suggesting that a polysaccharide vaccine could prevent these diseases. The young child is, however, unable to respond with antibody production to these polysaccharides, making such vaccines useless in infancy. Conjugation of the polysaccharide to a protein carrier has proven a way to solve the problem. Immunization of infants with such a Hib conjugate vaccine was shown in 1987 to result in the desired antibody production and protection from Hib meningitis and bacteremia. The Hib vaccine is now a part of national infant immunization programs in large parts of Europe, the Americas and Australia, and has resulted in the virtual disappearance of Hib disease from these areas. A group C meningococcal and 7-valent pneumococcal vaccine, available since 2000, are likewise proving highly effective in preventing bacteremic disease. Further advantages of the conjugate vaccines are their ability to elicit immunologic memory and to reduce asymptomatic carriage of the bacteria, resulting in marked herd immunity. This paper was delivered as a lecture in January 2003 in Bangkok on the occasion of the Prince Mahidol Award for a life's work in the field of vaccinology.     

Haemophilus influenzae meningitis in a child with complete immunisation

Invasive Haemophilus influenzae b (Hib) diseases are rarely observed in children with vaccination against Hib. Immunisation of infants against Hib was introduced in the Czech Republic in 2001. The first case of meningitis with isolation of Hib in child immunised with Hib vaccine since starting routine vaccination is described. Clinical course of meningitis was mild and was identical with previously manifestation of Hib meningitis.     

Immunological characterization of conjugated Haemophilus influenzae type b vaccine failure in infants.

Infant vaccination with conjugated Haemophilus influenzae type b (Hib) vaccine is highly effective in protecting against invasive Hib infections, but vaccine failures do occur. Twenty-one vaccine failures are reported since the introduction of the Hib conjugate vaccine in The Netherlands. Of the 14 evaluable patients, 6 children showed no antibody response to Hib polysaccharide in convalescent-phase serum (immunoglobulin [Ig] G anti-Hib level <1.0 microg/mL), including 1 child with hypogammaglobulinemia and 1 child with IgG2 deficiency. After revaccination, almost all children developed anti-Hib antibodies. In case of Hib vaccine failure, case investigation should be performed, including measurement of serum Ig concentrations as well as specific anti-Hib antibodies. Invasive Hib disease after infant conjugate Hib vaccination may be the presentation of an underlying immunodeficiency, but more often, only a decreased antibody response to Hib is found; revaccination with conjugated Hib vaccine is advised.     

Safety and immunogenicity of two doses of quadrivalent meningococcal conjugate vaccine or one dose of meningococcal group C conjugate vaccine,both administered concomitantly with routine immunization to 12- to 18-month-old children

OBJECTIVES:

To describe the immunogenicity and safety of a two-dose series of a quadrivalent meningococcal (serogroups A, C, Y and W) polysaccharide diphtheria toxoid conjugate vaccine (MenACYW-D) administered to toddlers.

METHODS:

Children were randomly assigned (1:1) at study entry to receive MenACYW-D at 12 and 18 months of age (group 1; n=61) or meningococcal serogroup C conjugate vaccine (MCC) at 12 months of age (group 2; n=62). All received routine childhood immunizations. A, C, Y and W antibody titres were measured in group 1 before and one month after the 18-month MenACYW-D vaccination and were measured in group 2 at one and seven months post-MCC vaccination. Antibodies elicited by diphtheria and tetanus toxoids, and acellular pertussis vaccine adsorbed combined with inactivated poliomyelitis vaccine and Haemophilus influenzae b conjugate (DTaP-IPV-Hib) vaccine coadministered at the 18-month vaccination were measured one month later. Safety data were collected.

RESULTS:

At 19 months of age, ≥96% in group 1 achieved protective titres for the four meningococcal serogroups after dose 2; 67% in group 2 exhibited protective titres against serogroup C 28 days after MCC vaccination at 12 months of age, declining to 27% seven months later. DTaP-IPV-Hib elicited high antibody concentrations/titres in groups 1 and 2, consistent with historical values. The safety profiles after each dose generated no unexpected safety signals; no serious adverse events were related to vaccination.

DISCUSSION:

A two-dose series of MenACYW-D given concomitantly with a DTaP-IPV-Hib booster dose at 18 months of age demonstrated a good immunogenicity and safety profile. A two-dose series of MenACYW-D can be used as an alternative to one dose of MCC and provides protection against additional serogroups (NCT ID: {"type":"clinical-trial","attrs":{"text":"NCT01359449","term_id":"NCT01359449"}}NCT01359449).     

Meningococcal carriage in the African meningitis belt

A meningococcal serogroup A polysaccharide/tetanus toxoid conjugate vaccine (PsA‐TT) (MenAfriVac^?) is being deployed in countries of the African meningitis belt. Experience with other polysaccharide/protein conjugate vaccines has shown that an important part of their success has been their ability to prevent the acquisition of pharyngeal carriage and hence to stop transmission and induce herd immunity. If PsA‐TT is to achieve the goal of preventing epidemics, it must be able to prevent the acquisition of pharyngeal carriage as well as invasive meningococcal disease and whether PsA‐TT can prevent pharyngeal carriage needs to be determined. To address this issue, a consortium (the African Meningococcal Carriage (MenAfriCar) consortium) was established in 2009 to investigate the pattern of meningococcal carriage in countries of the African meningitis belt prior to and after the introduction of PsA‐TT. This article describes how the consortium was established, its objectives and the standardised field and laboratory methods that were used to achieve these objectives. The experience of the MenAfriCar consortium will help in planning future studies on the epidemiology of meningococcal carriage in countries of the African meningitis belt and elsewhere.     

Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine

Widespread use of meningococcal AC polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to C polysaccharide. Whether meningococcal C conjugate (MCC) vaccine overcomes any immunologic refractoriness following MACP vaccination in adults was investigated. University students vaccinated 6 months previously with MACP vaccine were randomized to receive MACP or MCC vaccine, and antibody responses were compared with those of previously unvaccinated students receiving MACP or MCC vaccine. In students primed with MACP vaccine, MCC vaccine induced significantly higher IgG and serum bactericidal antibody levels than did a second dose of MACP vaccine. Responses to a second dose of MACP vaccine were significantly lower than to the first dose. Previous receipt of MACP vaccine reduced serum bactericidal antibody but not IgG responses to MCC vaccine compared with those in previously unvaccinated students. This confirms that MACP vaccine induces immunologic hyporesponsiveness to C polysaccharide in adults, but this can be overcome with MCC vaccine. Repeated vaccination with MACP vaccine may be ineffective, and MCC vaccines should provide better long-term protection.     

Meningococcal disease: risk for international travellers and vaccine strategies

International travel and migration facilitate the rapid intercontinental spread of meningococcal disease. Serogroup A and, less so serogroup C, have been responsible for epidemics in the past (mainly in Africa). In recent years, W135 has emerged (first in Saudi Arabia, then in West Africa) as a serogroup that requires attention. Serogroups X and Y are infrequent, but associated with slowly rising trends. There are significant variations in the incidence of meningococcal disease and the distribution of serogroups responsible for meningococcal disease, both geographically and with time. Vaccine strategies need to address this variation, and broad coverage against all serogroups for which vaccines are currently available should be offered to travellers. Tetravalent polysaccharide meningococcal vaccines are limited by their poor immunogenicity in small infants and by the lack of long-term protection. In contrast, the novel tetravalent conjugate vaccine that is currently only available in North America is immunogenic in young infants, induces long-term protection and reduces nasopharyngeal carriage. The tetravalent conjugate meningococcal vaccine will be a leap forward in the control of meningococcal epidemics in affected countries. It will also boost the uptake of meningococcal vaccines in travellers because the duration of protection is longer and it eliminates the problem of immune hyporesponsiveness of serogroup C with repeated dosing. Current vaccine recommendations are to vaccinate all Hajj pilgrims, all travellers to areas with current outbreaks, travellers to the SubSaharan meningitis belt, and individuals with certain medical conditions.     

Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction

The meningococcal serogroup C conjugate (MCC) vaccine programme in England has successfully controlled the incidence of serogroup C disease, as a result of high short-term vaccine effectiveness and substantial herd immunity. However, the long-term effectiveness of the vaccine remains unknown. We assessed surveillance data from the 4 years since introduction of the programme. Vaccine effectiveness remained high in children vaccinated in the catch-up campaign (aged 5 months to 18 years). However, for children vaccinated in the routine infant immunisation programme, the effectiveness of the MCC vaccine fell to low levels after only 1 year. The number of individuals in these cohorts remains low, but alternative routine immunisation schedules should be considered to ensure high levels of protection are sustained.