NmVac4-A/C/Y/W-135 – DT

NmVac4-A/C/Y/W-135 – DT

NmVac4-A/C/Y/W-135-DT is the commercial name of the Meningococcal meningitis polysaccharide serogroups A.C.Y.W-135 Diphtheria (DT) conjugate vaccine of JN-International Medical Corporation. The product is designed and formulated to protect populations during Meningitis disease epidemics in developing countries. Meningococcal groups A C Y and W-135 DT conjugate vaccines were developed using a genetically detoxified Diphtheria Toxoid as the protein carrier. This product uses standard procedures to produce non-chemically depolymerized polysaccharides by means of sonication. Micro-polysaccharides of 5100 to 9900 Daltons are coupled with purified Diphtheria Toxoid by reductive amination.[1] The product is specially designed and formulated to protect humans of all ages including children below the age group of 2 years against N. meningitidis serogroups A, C, Y and W-135 bacteria. The protein conjugate polysaccharide vaccines provide longer lasting protection against the disease compare to plain polysaccharide vaccines - NmVac4-A/C/Y/W-135, Mencevax and Menomune-A/C/Y/W-135. Menactra Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine of Sanofi Pasteur is the only FDA approved conjugate Meningitis vaccine in the United States.

Clinical Trials

Safety and immunogenicity of the NmVac4-A/C/Y/W-135 -DT quadrivalent conjugate meningococcal vaccine is being studied for its ability to elicit a protective immune response. All clinical trial protocols were evaluated and approved by an Institutional Review Board and Ethics Committee and the Ministry of Health, Ivory Coast. The human trials were conducted in Ivory Coast using 100 children for period of 48 weeks. Protective sero-conversion was recorded in 98% of individuals tested by Pasteure Research Institute. Diphtheria Toxoid was chosen for low-cost vaccine production. The vaccine had a tremendous impact on the incidence of the disease, resulting in a more than 90% decrease in the number of deaths and clinical cases, and a 66% decrease in asymptomatic carriage[2]

The Vaccine Safety - Advocacy

Polysaccharides themselves are poor at stimulating an effective antibody response in the highest risk age groups (infants). Coupling T cell independent polysaccharides to a T-cell dependent protein allows the infant immune system to provide T-cell help to B-cells to produce a boostable IgG antibody of high affinity to the polysaccharide antigen. T-Independent antigens are immunologically important. Molecules such as polysaccharides that have numerous identical evenly spaced epitopes characterize one type of TI antigen. As clusters of B-cell receptors bind the antigen simultaneously; it causes B-cell activation without the help of T-helper cells. Young children respond poorly to these antigens. Children less than two years of age are more susceptible to diseases caused by microbes that have polysaccharide capsules such as Neisseria meningitidis.[3]

Guillain-Barre syndrome among recipients of meningococcal conjugate vaccine was reported in the United States.[4] NmVac4-A/C/Y/W-135 – DT may cause the same syndrome. Due to lack of Phase-4 studies, one cannot exclude such side effect from NmVac4-A/C/Y/W-135 – DT immunization. As compare to Menactra, NmVac4-A/C/Y/W-135 – DT contains half the quantity or lower dose of polysaccharide and conjugate protein and which is the same quantity used in Hib conjugate vaccines.[3]

Thousands of children and adults in the sub-Saharan Africa contracted several infectious diseases such as meningitis, diphtheria, poliomyelitis or measles each year, vaccine safety concerns were not very common in this part of the world. People were more afraid of the childhood diseases than of possible side effects of the vaccines. In the past several years there has been a shortage on a variety of vaccines in Africa.[5] It has become increasingly difficult to keep certain vaccines on hand in storage. Vaccine orders take weeks or months to fill. Neisseria meningitidis is the main causative pathogen of meningitis epidemics in sub-Saharan Africa during December to April. Mass vaccination campaigns with polysaccharide vaccines are key elements in controlling these epidemics than vaccine safety concerns.[6] Due to extreme meningitis vaccine shortage, a fractional doses of tetravalent A/C/Y/W135 Meningococcal Polysaccharide Vaccine has been recommended for Africa.

Formulation

Meningococcal meningitis A/C/Y/W-135 conjugated to Diphtheria Toxoid vaccine is manufactured as a sterile, clear to slightly turbid liquid and is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 2 mcg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 24 mcg of diphtheria toxoid protein carrier.


Induction of Immunologic Memory by Conjugated vs Plain Meningococcal Polysaccharide Vaccine in infants

Neisseria meningitidis capsular polysaccharides are poor immunogens particularly in young infants. However, conjugation of bacterial polysaccharides to immunogenic carrier proteins generally results in conjugates that induce strong anti-polysaccharide T-helper cell dependent immune responses in young infants. The magnitude of the response and the extent of the T-helper-cell dependency is related to the chemical characteristics of the particular conjugate such as presence or absence of polysaccharide-protein cross-linking, presence or absence of spacer arms, character of spacer arms, type of carrier protein, size of conjugated polysaccharide hapten, and molar degree of substitution.

Fig 1. Purified polysaccharide vaccines activate immune system to produce protective and circulating antibodies against the disease. At the time of disease initiation, these protective antibodies would phagocyze the disease causing bacterial capsules and eliminate bacteria through macrophages and neutrophils. B cells in a thymus-independent type 2 (TI-2) reaction are activated by polysaccharides and the cross-linked antibodies on the B cell surface, which leads to the formation of plasma B cells and antibodies without the help of helper T cells. Just a T independent immune activation system triggers IgM production without class switching resulting in little development of memory cells. Therefore, vaccines composed solely of purified polysaccharides are only effective in older children and adults for 18 months.[7] Due to immature immune systems of infants and children less than two years of age cannot get effective immune response from pure polysaccharide immunization and cannot respond to bacteria causing meningitis.

Fig 2. Protein such as Diphtheria Toxoid linked to purified bacterial polysaccharides by conjugation and these purified protein carriers engage helper T cells in the polysaccharide antigen response. In addition, the protein carrier of the conjugate vaccine leads to antigen presentation on antigen presenting B cells. The interface of the B cells with T helper cells induces class switching from IgM to IgG, which creates longer-lasting specific immune response against Meningitis disease.[8][9][10]

References