review
Human Vaccines 7:2, 170-182; February 2011; © 2011 Landes Bioscience
Meningococcal glycoconjugate vaccines Roberto Gasparini* and Donatella Panatto Department of Health Sciences; Genoa University; Genoa, Italy
Key words: meningococcus, Neisseria meningitidis, glycoconjugate vaccines, meningococcal disease, immunity, vaccination Abbreviations: ACIP, advisory committee on immunization practices; AE, adverse event; CDC, US Center for Disease Control and Prevention; CRM 197, a nontoxic variant of diphtheria toxin; CSF, cerebrospinal fluid; DT, diphtheria toxoid; dTaP, diphtheria (dose for adult), tetanus and acellular pertussis vaccine; DTaP, diphtheria (dose for children), tetanus and acellular pertussis vaccine; EMEA or EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; fH, factor H; fHBP, factor H Binding protein; GAVI, global alliance for vaccines and immunization; GBS, Guillain-Barrè syndrome; GMT, geometric mean titer; Hib, Haemophilus influenzae type b; HPA, UK Health Protection Agency; hSBA, serum bactericidal antibody assay with human complement; MC-4, quadrivalent A,C,W-135 and Y conjugate (dipheria toxoid as carrier) vaccine, usually used for Menactra™; MCC, meningococcal C conjugate vaccine; MCV4, quadrivalent A,C,W-135 and Y conjugate (diphtheria toxoid as carrier) vaccine; Men A-TT, meningococcal A tetanus toxoid conjugate vaccine; MenA, meningococcal A conjugate vaccine; MenACWY-CRM197, quadrivalent A,C,W-135 and Y conjugate (CRM 197 as carrier) vaccine; MenACWYTT, quadrivalent A,C,W-135 and Y vaccine conjugated with tetanus toxoid; MenC, meningococcal C conjugate vaccine; MLTS, multilocus sequence typing; Mn A, group A meningitis; MPS-4, plain tetravalent A,C,W-135 and Y meningococcal vaccine; MPSV4, plain tetravalent A,C,W-135 and Y meningococcal vaccine; MVP, meningitis vaccine project; NACI, Canadian National Advisory Committee on Immunization; NMB, Neisseria meningitidis group B; OMP, complex outer-membrane protein mixture derived from N. meningitidis; PATH, program for appropriate technology in health; PS, polysaccharide; PsA-TT, meningococcal A tetanus toxoid conjugate vaccine; rSBA, serum bactericidal antibody assay with rabbit complement; SAE, serious adverse events; SBA, serum bactericidal antibody assay; siaDb or siaDB, polysialyltransferase gene (siaD) for serogroup B N. meningitidis; siaDc or siaDC, polysialyltransferase gene (siaD) for serogroup C N. meningitidis; SIIL, Serum Institute of India Ltd.; ST-11, sequence type-11 complex; TD, T cell-dependent; TI, T cell-independent; TT, tetanus toxoid; UK, United Kingdom; USA, United States of America; VAERS, vaccine adverse event reporting system; VFs, virulence factors; WHO, World Health Organization
Neisseria meningitidis is a major cause of invasive bacterial infections worldwide. For this reason, efforts to control the disease have been directed at optimizing meningococcal vaccines and implementing appropriate vaccination policies. In the past, plain polysaccharide vaccines containing purified capsular polysaccharides A, C, Y and W135 were developed, but failed to protect infants, who are at greatest risk. Experience with the conjugate Haemophilus vaccine suggested that this approach might well empower meningococcal vaccines. Thus, a very efficacious vaccine against serogroup C Neisseria meningitidis was optimized and has been widely used in developed nations since 1999. On the basis of epidemiological changes in the circulation of pathogenic serogroups in the United States, a quadrivalent conjugate vaccine against A, C, Y and W135 serogroups (MenactraTM) has been developed and was approved by the US FDA (Food and Drug Administration) in 2005. Recently, another tetravalent conjugate meningococcal vaccine (MenveoTM) has been licensed and made available in the United States of America and in the European Union.
*Correspondence to: Roberto Gasparini; Email:
[email protected] Submitted: 06/18/10; Revised: 09/13/10; Accepted: 09/22/10 DOI: 10.4161/hv.7.2.13717
170
Finally, in response to large epidemics caused by serogroup A meningococcus in Africa, a new, safe, immunogenic and affordable vaccine has been developed. This review highlights the evolution of conjugate meningococcal vaccines in general and discusses how this kind of vaccine can contribute to preventing meningococcal disease.
Introduction Although two centuries have passed since Vieusseux first described epidemic meningococcal disease,1 Neisseria meningitidis remains a major and insidious cause of death, even in industrialized countries. Indeed, meningococcal disease can develop extremely rapidly and is associated with a high case-fatality rate, although antibiotics, such as rifampicin or cephalosporins, usually have great bactericidal efficacy. However, some antibiotic resistance has recently been reported (e.g., ciprofloxacin resistance).2 For this reason, efforts to control the disease have been directed at optimizing meningococcal vaccines and implementing appropriate vaccination policies. Plain polysaccharide vaccines have failed to protect infants, who are at greatest risk. Experience with the conjugate Haemophilus vaccine suggested that this approach might empower meningococcal vaccines too. Thus, a very efficacious vaccine against type C Neisseria meningitidis was optimized
Human Vaccines Volume 7 Issue 2
REVIEW
review
and has been widely used in developed nations since 1999.3,4 Multivalent–conjugate (7- 10- and 13-valent) vaccines against S. pneumoniae have also been developed.5-7 Recently, two tetravalent (against A, C, Y and W135 serogroups) conjugate meningococcal vaccines (MenactraTM and MenveoTM) 8,9 have been licensed and made available in the United States of America (USA) and MenveoTM in the European Union (EU).10 Neisseria meningitidis is a bacterium that is only pathogenic in humans. It colonizes the nasopharynx and can be transmitted from person to person by direct contact with respiratory secretions or saliva, or via aerosol droplets.11 Adolescents and young adults constitute the greatest proportion of carriers.12-14 Meningococci have a polysaccharide capsule that protects them from desiccation and immune-mediated host defenses.15 Pili extend from the outer membrane and through the capsule to facilitate the initial attachment of meningococci to human cells and their movement over epithelial surfaces. Classification of N. meningitidis into serogroups is based on the immunologic reactivity of their capsular polysaccharides; 13 serogroups have been identified: A, B, C, Y, W135, X, D, 29E, H, I, K, L and Z, although only the first six are involved in human pathology.16 Because the polysaccharides are the major meningococcal virulence factor (for instance polysaccharides are involved in the resistance of the bacterium against antimicrobial peptides and encapsulated wild-type N. meningitidis have substantially reduced adherence to dendritic cells compared with unencapsulated strains17-19) and because they are the outermost antigens on the surface of the bacterium, all licensed vaccines contain one or more A,C,W and Y polysaccharides. Although the conjugate vaccines against meningitidis diseases have improved coverage for infants and adolescents, broadly effective meningococcal B vaccines are not yet available. This is a crucial fact, as Neisseria meningitidis group B (NMB) is now a predominant cause of the disease in industrialized countries.20,21 Recent research into N. meningitidis genomics and reverse vaccinology may be able to solve this seemingly intractable problem.22-27 This review highlights the evolution of conjugate meningococcal vaccines in general and discusses how this kind of vaccine can contribute to containing meningococcal disease. Epidemiology As for other bacteria, our knowledge of meningitis pathogenesis has rapidly expanded in recent decades. The capacity of N. meningitidis to colonize humans efficiently depends on its ability to evade the immune system. Indeed, its extensive variation of surface antigens, resistance to antimicrobial molecules, such as LL-37, resistance to complement, etc., are important mechanisms of survival for N. meningitidis in its sole niche of life.17 Transmission of N. meningitidis often leads to transient asymptomatic carriage. Carriers are the reservoir of the bacterium and, for this reason, may be regarded as the focus of infection control measures.28 Although carriage is relatively common, the majority of carriers do not acquire serious invasive disease. Only when N. meningitidis passes through the mucosa into the bloodstream and subsequently moves into the cerebrospinal fluid
www.landesbioscience.com
(CSF) can the patient develop invasive disease.29 This unfortunate event can be determined by a concurrence of different situations of risk, such as: asplenia, properdin deficiency, complement deficiency or depletion (C3, C5-9), previous or concomitant viral respiratory tract infection (influenza virus neuroaminidase could favor the adhesion of the bacterium to the surface of respiratory cells), chronic underlying disease, young age, crowded environmental conditions (e.g., discothèques, pubs, dormitories, etc.), living in close contact with others (e.g., students, military recruits, crowded homes), low socio-economic status, close contact with a patient or a carrier, travel to regions with a higher risk of meningococcal infection (e.g., African meningitis belt territories) and occupational exposure (e.g., healthcare or laboratory workers).29-31 The epidemiology of meningitis is very variable. In industrialized nations morbidity ranges from 0.2 to 4.7 cases per 100,000 inhabitants, whereas in sub-Saharan Africa and in the territories of the “meningitis belt” epidemics involve from 100 up to over 1,000 cases per 100,000 population.21,32 In the pre-antibiotic era, the meningitis case-fatality rate ranged from 70 to 90%; nowadays, it is estimated to be 7–14%. However, up to 20% of survivors suffer permanent sequelae. For example, a retrospective survey carried out in the province of Quebec, Canada, on 304 cases that occurred in 1990–94 reported a case-fatality rate of 14.0% and a percentage of sequelae of 15.3% (scarring 11.5%, amputation 4.6%, hearing loss 1.9% and renal failure 1.1%).15,33-35 From Polysaccharide Plain Vaccines to Conjugate Meningococcal Vaccines Early attempts to develop vaccines against N. meningitidis were made from 1900 to 1940, using killed whole bacteria.36,37 Excessive reactogenicity, uncertainty as to the immunity conferred by these preparations, and the successes of treatment and prevention by means of antibiotics delayed the development of new vaccines. Subsequently, however, the phenomenon of sulfonamide-resistance38,39 prompted renewed interest in developing meningococcal vaccines. Indeed, at the end of the 1960s, Gotschlich et al. developed a new approach to purifying high molecular-weight meningococcal polysaccharides, which were thus rendered safe and immunogenic in humans.40,41 Meningococcal capsular polysaccharides purified in this manner are the basis of the currently licensed bivalent (A and C) and quadrivalent (A, C, Y and W-135) polysaccharide vaccines. Plain meningococcal vaccines are licensed in bivalent (groups A and C [Meningivac™]) and quadrivalent (groups A, C, W135 and Y [Menomune™ and ACWYVax™]) formulations. GlaxoSmithKline Biologicals has developed a trivalent preparation (groups A, C and W-135) only for use in W135 epidemics that occur in sub-Saharan Africa. Immunity elicited by meningococcal serogroups A, C, Y and W-135 is serogroup-specific. The efficacy of N. meningitidis serogroup A polysaccharide vaccine has proved to be 89–100% in clinical trials (army recruits and children aged three months to five years).42,43 Group A and C polysaccharide vaccines displayed
Human Vaccines
171
85% efficacy in clinical trials performed in settings in which meningococcal disease was epidemic.44 When polysaccharides Y and W-135 were used, they proved immunogenic only in subjects over two years of age.45,46 Meningococcal plain polysaccharide vaccines have shown a good safety profile, the most common adverse events being mild.47,48 Polysaccharide vaccines have yielded good results in army recruits. For instance, a bivalent vaccine for Italian army recruits introduced in 1987 (since 1991 tetravalent preparations have been used) displayed 90% efficacy,49 leading to a dramatic reduction in cases in the population of the Italian army.49 Because most cases of meningitis in Africa are sustained by serogroup A N. meningitidis, polysaccharide meningococcal vaccines have been used in several circumstances. In 2003, Robbins et al.50 suggested the use of meningococcal polysaccharide vaccine twice in infancy, followed by quadrivalent vaccine in children aged from two to six years. However, as underlined by Birmingham et al.51 this policy could be ineffective and possibly harmful. Indeed, many studies have described the short-lived immunity provided by group A meningococcal polysaccharide vaccine, its poor immunogenicity in young children, and the fact that multiple doses of group A meningococcal polysaccharide vaccine in childhood may actually attenuate the serum bactericidal antibody response to N. meningitidis. Indeed, the principal limitation of polysaccharide plain vaccines is that they do not stimulate the T- cell and so do not induce immunologic memory. Because of the above-mentioned deficiencies, meningococcal conjugate polysaccharide vaccines have been studied since the mid-1990s.52,53 Carbohydrate-Protein Conjugate Vaccines In 1929, Avery and Goebel showed that conjugating a bacterial polysaccharide with a carrier protein elicited a stronger antibody response to the carbohydrate moiety.54 The discovery of T helper cells and their role in helping B cells to produce antibodies enabled antigens to be classified as T- cell-independent (TI) or T- cell-dependent (TD).55 With TD antigens, an immune response occurs at birth or shortly afterwards, affinity maturation of the B- cell response takes place, immunologic memory occurs and adjuvants can induce an enhanced response.56 TI antigens are divided into two groups. The first group comprises B- cell mitogens and includes polysaccharides. The second group comprises polysaccharides which have repeating epitopes. Antigens of the second group induce an immune response only 3–18 months after birth and infants (less than two years of age) generally have a poor response; IgM is mainly elicited and produced in the spleen57 and there is no affinity maturation of the antibody response, no immunologic memory and no enhancement of response by adjuvants. Several immunogenic proteins have been studied, but only five have been used: diphtheria (D) or tetanus (T) toxoid, CRM 197 (a non-toxin variant of diphtheria toxin), OMP: a complex outermembrane protein mixture derived from the B11 strain of N. meningitidis serogroup B and protein D, derived from non-typeable Haemophilus influenzae (NTHi). Furthermore, the Pseudomonas
172
aeruginosa recombinant exoprotein A (rEPA) appears to be another promising potential carrier protein. The polysaccharides or an oligosaccharide are linked to the carrier. H. influenzae type b (Hib), the first conjugate vaccine to be prepared, was developed in 1992.58 Three preparations were licensed in the USA (conjugated with CRM 197, tetanus toxoid and OMPs, respectively). These vaccines are highly immunogenic in infants and immunocompromised persons, and they are 95–100% effective in eliminating all Hib disease when used in the routine infant vaccination schedule.59-63 Subsequently, pneumococcal conjugate vaccines were developed. Pneumococcal conjugate vaccines require the individual conjugation of each serotype with a carrier protein. There are 90 different serotypes, with different capsular polysaccharides, but only 7–13 are very important for human pathology. A heptavalent conjugate (using CRM 197 as a carrier) vaccine has been licensed in the USA and Europe,5 and another six polysaccharides have recently been added.7 Another conjugate pneumococcal vaccine that has recently been licensed in Europe is a 10-valent vaccine6 absorbed on aluminum phosphate and conjugated with tetanus toxoid, diphtheria toxoid and protein D derived from nontypeable Haemophilus influenzae. These preparations are highly protective against invasive disease and offers partial protection against other diseases, such as pneumonia and otitis media, caused by S. pneumoniae.64,65 Apart from meningococcal vaccines, which are the focus of this review and which are considered in greater detail in the following sections, other polysaccharide vaccines are under study, such as vaccines against: Salmonella typhi,66 Group B Streptococcus,67 Staphylococcus aureus,68 and Escherichia coli.69 Table 1 provides a summary of carbohydrate-protein conjugate vaccines and meningococcal conjugate vaccines. Conjugate Vaccines against Meningococci The diversity and molecular mimicry of N. meningitidis strains have been the main obstacle to developing meningococcal vaccines. The available anti-meningococci vaccines, which contain purified capsular polysaccharides A, C, W135 and Y, are not so effective in eliciting immunological memory or generating an effective immune response in infants.70,71 Conjugating capsular polysaccharides with carrier protein enabled these problems to be overcome, first with regard to N. meningitidis of group C and subsequently for groups A, W135 and Y. However, the very insidious mimicry of Neisseria of group B has thwarted any such solution for this type of bacteria. Recently, Novartis has developed a new vaccine containing five antigens; one of these, named fHBP (factor H Binding Protein), is contained in another new vaccine developed by Wyeth. These encouraging products are currently being assessed in phase II and III clinical trials.27 Meningococcal serogroup C conjugate vaccines were introduced for infants, toddlers and teenagers in the UK beginning in 1999.72 The licensed preparations are conjugated with CRM 197 protein or tetanus toxoid. Before the MenC conjugate vaccine was licensed, the incidence of meningococcal disease in developed countries ranged
Human Vaccines Volume 7 Issue 2
Table 1. A summary of carbohydrate-protein conjugate vaccines and meningococcal conjugate vaccines Formulation, vaccine
Reference(s)
Available licensed (HibTiter )
59–63
Hib type b polysaccharide conjugated tetanus toxoid with + MenC polysaccharide conjugated with tetanus toxoid
77
Men C conjugated with CRM197 Men C conjugated with CRM197 Men C conjugated with tetanus toxoid Men C conjugated with CRM197
Men A, C, W-135 and Y polysaccharide conjugated with diphtheria toxoid Men A, C, W-135 and Y polysaccharide conjugated with CRM-197
Men A polysaccharide conjugated with Tetanus Toxoid
*
Results ™
Hib type b polysaccharide conjugated with CRM 197* Hib type b polysaccharide conjugated with CRM 197* Hib type b polysaccharide conjugated with tetanus toxoid Hib type b polysaccharide conjugated with tetanus toxoid Hib type b polysaccharide conjugated with OMP**
S. pneumoniae 7 polysaccharides Conjugated with CRM197 S. pneumoniae 13 polysaccharides Conjugated with CRM197 S. pneumoniae 10 polysaccharides Conjugated with protein D (derived from non-typeable Hib), tetanus toxoid and diphtheria toxoid. Other S. pneumoniae polysaccharide vaccines have been licensed in the past, such as 8-valent, 9-valent and 11-valent vaccines.
Clinical status
Available licensed (Vaxem Hib™) Available licensed (Acthib™) Available licensed (Hiberix™)
These vaccines are highly immunogenic in infants and in immunocompromised persons, and are 95-100% effective in eliminating all Hib diseases when used in the routine infant vaccination schedule.
Available licensed (PedvaxHIB™) Available licensed (Menitorix™)
Administered at 6 years of age, elicited a very high antibody response in children who had received conjugate MenC in infancy.
Available licensed (Prevenar™)
Available licensed (Synflorix™)
These vaccines confer very high protection against invasive disease, and partial protection against other diseases, such as pneumoniae and otitis media. The replacement phenomenon was observed after wide use of the heptavalent vaccine.
Available licensed (Menjugate™) Available licensed (Meningitec™) Available licensed (Neis-vac™) Available licensed (Meninvact™)
After the introduction of Men C conjugate vaccine, the incidence of invasive disease fell dramatically; a decrease in nasopharyngeal carriage was also evident. However, while antibody response was sustained in adolescents, it rapidly waned in young children. This suggests the need for a booster dose for 6- and 12-year-olds.
79–87 88–93
Available licensed (Menactra™) Available licensed (Menveo™)
Menactra™ is effective in adolescents and young adults but its immunogenicity is poor in infants. MenACWY-CRM has a good immunogenic power in children, young adults and subjects up to 65 years of age. Furthermore, it is possible to co-administer MenACWY-CRM with dTaP and HPV vaccines.
100–105
WHO prequalification obtained; Regional (Maharashstra State—India) FDA authorization obtained (MenAfriVac™); Regulatory file submitted to Drug Controller General of India (DCGI)
The vaccine has proved safe and highly immunogenic in clinical trials on animals, adults, infants, young children and subjects aged up to 29 years.
Available licensed (Prevenar-13™) 5–7
4, 72–78
a non-toxin variant of diphtheria toxin. **a complex outer-membrane protein mixture derived from N. meningitidis.
from
