Neisseria meningitidis vaccines

Organizations involved:

Cross ref: See the entries below for particular meningococcal vaccines.

Description: Meningococcal Polysaccharide Vaccines are Neisseria meningitidis polysaccharide vaccines used for prevention of meningococcal (Neisseria meningitidis) disease. These vaccines contain cultured, inactivated, and purified N. meningitidis bacteria capsular (outer membrane) polysaccharides from N. meningitidis stains A-1, C-11, 6306Y, and W-135-6308 (representing groups A, C, Y and W-135, respectively), either alone or in combination.

Nomenclature: Meningococcal Polysaccharide Vaccines is the FDA proper name (generic name) for these vaccines.

Biological.: The N. meningitidis group A polysaccharide consists partly of a polymer of N-acetyl-O-acetyl mannosamine phosphate (O-acetylated repeating units of N-acetyl-man-nosamine, linked with 1-->6 phosphodiester bonds). N. men-in-gitidis group C polysaccharide consists of partly O-acetylated repeating units of sialic acid, linked with 2-->9 glycosidic bonds, mostly over 100,000 Dalton (100 kDa) in weight. N. meningitidis group Y polysaccharide consists of partly O-acety-lated alternating units of sialic acid and D-glucose, linked with 2-->6 and 1-->4 glycosidic bonds. N. menin-gitidis group W135 polysaccharide consists of partly O-acetylated alternating units of sialic acid and D-galactose, linked with 2-->6 and 1-->4 glycosidic bonds. The bacterial polysaccharide components, together with calcium ions and residual moisture, account for nearly all of the mass of these vaccines. Immunogenicity of the polysaccharide polymers increases with their molecular weight/size.

These vaccines provide protection by inducing N. meningitidis bacteria strain-specific neutralizing antibodies. The ability of polyvalent meningococcal vaccines to induce antibodies and/or prevent disease in clinical field trials has been shown to be related to composition, purity, and potency.

History: Organizations having received approval in 1914 for manufacture of Meningococcus Vaccine were Dept. of Health, New York City; Cutter Labs.; E.R. Squibb & Sons, Inc.; Lederle Labs., Parke, Davis & Co.; and Sherman Labs. (based on FDA listings, which contain many errors/omissions for vaccines prior to the mid 1970s, when FDA assumed biologics regulation from NIH).

Conventional (not conjugated to protein carrier) N. men-ingi-tidis (meningococcal) group A and group C vaccines were originally developed at the Walter Reed Army Institute of Research (WRAIR), U.S. Army – a subgroup C vaccine in the late 1960s and later a subgroup A vaccine. Prior to licensure in the U.S., these vaccines were administered to nearly the entire populations of Finland and Brazil (tens of millions of people) to stop epidemics. The U.S. military adopted vaccination for its personnel in 1971. Institut Merieux (now Sanofi Aventis S.A.) developed a subgroup A vaccine in the early 1970s.

Merck & Co., Inc. was licensed to manufacture Meningococcal Polysaccharide Vaccine, Group A from July 1975-March 1995. Merck & Co. was licensed to manufacture Meningococcal Polysaccharide Vaccine, Group C from April 1974-March 1995. Conventional Group A and a Group C vaccines were previously manufactured and marketed in the U.S. by E.R. Squibb & Sons, Inc. (dates unavailable).

Indications: See the entry for Meningococcal Poly-saccharide Vaccine, Groups A, C, Y, W135 Combined (#502) for the most extensive coverage of indications: for these vaccines from Sanofi Aventis.

Status: Meningococcal vaccines are currently not among the required/universal pediatric vaccines in the U.S., due largely to their lack of long-term efficacy in young children. Recent changes in U.S. guidelines, recommending it for all adolescents, are discussed in the Medical section below. Due to cost and its use in adolescents rather than infants, the federal government is not expected to make meningococcal vaccine, even with newer Menactra, a required/universal pediatric vaccine.

Meningitis group C is a required pediatric vaccine in Britain, where group C strains of N. meningitidis cause 40% of meningitis cases.

U.S. Pharmacopeia (USP) standards have been issued for the group A and C vaccines.

Trials: Numerous studies have demonstrated the immunogenicity and clinical efficacy of the A and C polysaccharide vaccines. The antibody responses to each of the four polysaccharides in the quadravalent vaccine are serogroup-specific and independent. The serogroup A polysaccharide induces antibody in some children as young as 3 months of age, although a response comparable to that seen in adults is not achieved until 4 or 5 years of age. The serogroup C component does not induce a good antibody response before age 18-24 months.

The serogroup A polysaccharide vaccine has been shown to have a clinical efficacy of 85%-95%, and to be useful in controlling epidemics. A similar level of clinical efficacy has been demonstrated for the serogroup C vaccine, both in American military recruits and in an epidemic. The group Y and W-135 polysaccharides have been shown to be safe and immunogenic in adults and in children over 2 years of age. Clinical efficacy for group Y and W-135 polysaccharides has not been demonstrated directly, but is assumed, based on the induction of bacteria-neutralizing antibody, which for group C has been correlated with clinical protection. Four-fold increases in bacteria-neutralizing antibody to serogroups A, C, Y and W135 were generally observed in at least 90% of subjects tested.

Disease: Neisseria meningitis is an aerobic, Gram-negative, diplococcus member of the Neisseriaceae family of bacteria. N. meningitidis causes both endemic and epidemic disease, principally meningitis (brain/nervous system infection) and meningococcemia (bloodstream infection). Meningococcal infection is the second most common cause of bacterial meningitis in the U.S. (approximately 20% of all cases), affecting an estimated 3,000-4,000 people each year. The case-fatality rate is approximately 10% for meningococcal meningitis and 20% for menin-go-coccemia, despite therapy with anti-biotics, e.g., penicillin, to which all strains remain highly sensitive, with an overall fatality rate of about 10%-15%. From 11%-19% of survivors have significant sequelae, including neurologic disability, limb loss, or hearing loss.

Meningococcal disease is primarily caused by five sero-groups of Neisseria meningitidis: A, B, C, Y and W-135. In the U.S. and world-wide, 90% of meningitis is due to meningo-cocci sero-groups A, B and C, with the remaining cases due to Y and W135. There currently is no vaccine for serogroup B.

Meningococci bacteria are quite common, including residing in the back of the nose and throat of “healthy carriers,” about 20% of adolescents and adults, without causing any illness (asymptomatic). Spread of meningococci most often involves healthy carriers, rather than those with visible disease. Spread from an infected person to another requires close, direct contact through activities such as kissing, coughing and sneezing; or spread through saliva when sharing items such as cigarettes, lipstick, food or drinks, cups, water bottles, cans, drinking straws, toothbrushes, toys, etc. The risk of spread is increased by smoking and overcrowding.

Meningococcal disease current kills nearly 3,000 people in the U.S., most of them adolescents and teenagers. The populations at risk for meningococcal infection include adults, young children, and infants. The disease incidence peaks each year during the winter (Feb.-March). Epidemics are rare in the U.S., with most cases sporadic and not associated with outbreaks. The last major U.S. epidemic of meningococcal disease was in 1946. Attack rates are highest among children aged 6-12 months and then steadily decline by age 5 years, and the incidence approximates that for adults. However, unlike adults, young children generally respond poorly to unconjugated bacterial polysaccharide vaccines, and meningococcal vaccines is not a universal or required pediatric vaccine.

Serogroup B, for which a vaccine is not yet available, accounts for 50%-55% of all U.S. cases; serogroup C, for 20%-25%; and serogroup W-135, for 15%. Serogroups Y (10%) and A (1%-2%) account for nearly all remaining cases. Serogroup W-135 has emerged as a major cause of disease in the U.S. only since 1975. While serogroup A causes only a small proportion of endemic disease in the U.S. it is the most common cause of epidemics elsewhere. Less commonly, serogroups C and B can also cause epidemics. The incidence of group C disease in the U.S. is about 0.5 cases/100,000 population/year.

Medical: Menomune, until 2005 the only available meningococcal vaccine, provides protection only for a few years, and it is minimally effective in young children. Menactra, approved in 2005, is the first available meningococcal vaccine to provide long-lasting immunity.

Despite the availability of vaccines, antimicrobial chemoprophylaxis (antibiotic treatment, e.g., with rif-am-pin) of intimate contacts remains the chief preventive measure for the sporadic cases of N. meningitidis in the U.S. Intimate contacts include (1) household members, (2) day-care-center contacts, and (3) anyone directly exposed to the patient’s oral secretions, such as through mouth-to-mouth resuscitation or kissing. The attack rate for household contacts is 0.3%-1%, 300-1000 times the rate in the general population. Systemic antimicrobial therapy of meningococcal disease does not reliably eradicate nasopharyngeal carriage and transmission of N. meningitidis.

Endemic meningococcal disease is very uncommon above age 5 years. However, older children, adolescents, and young adults constitute a higher proportion of cases during epidemics and may warrant vaccination during an outbreak.

Primary immunization with polysaccharide vaccine for both adults and children involves administration one-time subcutaneously of a single 0.5 mL dose, with no subsequent booster. In some cases, children at high risk may receive a second vaccination. Protective levels of neutralizing antibody generally appear in about 7-10 days. Antibodies against the group A and C polysaccharides decline markedly over the first 3 years following a single dose of polysaccharide vaccine, and a booster shot may be needed for those at high risk.

Routine vaccination of civilians with meningococcal poly-saccharide vaccine is not recommended in the U.S. for the following reasons: (1) the risk of infection in the U.S. is low; (2) a vaccine against serogroup B, the major cause of meningococcal disease in the U.S,, is not available; and (3) much of the meningococcal disease in the U.S, occurs among children too young to benefit from vaccines. Other persons with acquired immune deficiency, e.g., from HIV-infection or cancer chemotherapy treatment, may also receive vaccines. Vaccines have been shown to be of use in aborting outbreaks due to sero-groups represented in the vaccine.

A number of states in the U.S. have adopted laws requiring college attendees to receive meningococcal vaccine. Cases of meningococcal infection and deaths among U.S. college students have resulted in much media attention and recommendations that college students receive or consider vaccination (with a vaccine covering types A/C/Y/W-135). Although a threat to older teens and young adults and with small outbreaks and deaths from meningococcal disease generally making the news each year, vaccine (Meno-mune-A/C/Y/W-135 or Menactra) is not recommended for widespread use by this generally healthy population. This will likely change, once newer vaccines with longer periods of efficacy, e.g., able to provide protection from age 11 into early adulthood, become available. Many college students (or their parents) elect to receive type A,C, Y, W-135 vaccine, particularly since the few occasional cases/deaths due to meningococcal disease in this population are widely reported along with reminders that preventative vaccine is available.

Vaccination with the A/C combination vaccine may benefit some travelers to countries recognized as having hyperendemic or epidemic disease and those living in these areas, e.g., sub-Saharan Africa and other parts of the world.

Bivalent A/C vaccine is routinely administered by the Department of Defense (DOD) to those joining the military. In the past, new military recruits were at especially high risk, particularly for serogroup C disease. However, since routine vaccination of recruits with the bivalent A/C vaccine began in 1971, disease in the U.S. military caused by those serogroups has been uncommon.

In Jan. 2005, the Centers for Disease Control and Prevention (CDC) made meningococcal disease a Notifiable Disease by serotype, i.e., culture-confirmed and probable cases should be reported by individual serotype to state, territorial, and/or local health departments, which will report cased to CDC. Previous reporting did not include serotype characterization. Confirmed cases are those in which N. meningitidis is isolated from a normally sterile site (e.g., blood or cerebrospinal fluid, or less commonly, joint, pleural, or pericardial fluid). Probable cases of meningococcal disease include those with a positive antigen test in CSF or clinical purpura fulminans in the absence of a positive blood culture.

In Jan. 2008, the new 2008 Childhood and Adolescent Immunization Schedules released jointly by the U.S. Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the American Academy of Family Physicians updated the immunization schedule for vaccination against meningococcal disease. The Meningococcal Conjugate Vaccine (MCV4; Menomune-A/C/Y/W-135) was recommended for children 11 to 12 years of age and teens 13 to 18 years of age who haven't been previously vaccinated and other people at heightened risk of meningococcal disease, including college freshmen living in dorms, as well as military recruits. The goal is routine vaccination of all children beginning at age 11 years; with college freshmen living in dormitories vaccinated with MCV4 before college entry.

Market: The largest market opportunity for growth in sales of meningitis vaccines is the U.S., where meningococcal strains C and Y are major causes of disease in children under two years of age and recent recommendations now include vaccination of adolescents and teens. Hib-MenCY combination vaccine is being developed for children under age two, and could replace the current Hib vaccine and fit into the vaccine schedule with no additional injections. Hib-MenCY has shown an excellent safety profile, and 95% of infants who received the vaccine achieved levels of bactericidal (i.e., bacterial killing) antibodies known to correlate with clinical protection. GSK expects to submit Hib-MenCY for filing in 2008 in the US. FDA has granted the BLA fast-track status, allowing submission of portions of the BLA for review as they are completed.

GlaxoSmithKline (GSK) estimates that the global N. meningitidis market could increase over the next five years from its current value of approximately £150 million ($275 million) to £0.6-0.8 billion ($1.1-1.5 billion) by 2010, mostly due to growth in the US. Additionally, GSK submitted a file earlier this year to the UKauthorities for Menitorixand is awaiting approval. Menitorix will be rolled out across Europeafter approval in the UK. GSK’s other meningitis vaccines for global markets are scheduled for regulatory filings in 2006 and 2007.

Sanofi Aventis completely dominates the U.S. market for meningococcal vaccines (with vaccines from no other manufacturers on the market). In Sept. 2003, Aventis S.A. reported that its annual meningitis vaccine sales could eventually approach one billion euros (then $1.15 billion), particularly as its new multivalent toxoid conjugate vaccine, Menactra, was launched and more infants (and children and adolescents) are vaccinated, including anticipated future use in infants under the age of two years.

In the 1990s, experiencing an outbreak of meningitis C, the U.K. initiated a vaccine development incentive program similar in many respects to those proposed in the U.S. to stimulate development of new vaccines, including those for biodefense, and assure multiple suppliers of vaccines, which has proven to be a major concern with influenza vaccines (and others). With the U.K. government (as with the U.S. government) being the single largest purchaser of vaccines, it allocated pre-specified percentages of the market to the first, second and third new entrants. In 1996, the Department of Health announced a tender for 18 million doses, with the first to market to receive the largest share. Wyeth was the first to bring a vaccine to the U.K market in 1999, and was rewarded with a contract for 10 million doses. This was followed by Chiron in 2000, which received a contract for 5 million doses, and by Baxter Healthcare Corp. a few months later, which received a contract for 3 million doses. This appears to be the only precedent for a government in a major developed country successfully providing monetary incentive for private sector development of multiple vaccines for the same indication.

In Jan. 2008, the 2008 Childhood and Adolescent Immunization Schedules were released jointly by the U.S. Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the American Academy of Family Physicians. Changes included Meningococcal Conjugate Vaccine (MCV4) now recommended for children 11 to 12 years of age and teens 13 to 18 years of age who have not been previously vaccinated and other people at heightened risk of meningococcal disease, including college freshmen living in dorms, as well as military recruits.

Competition: See the entry below for recently-approved Menactra, which will likely capture the majority of the market for meningitis vaccines.

R&D: In Jan. 2004, Chiron Vaccines, Chiron Corp., now Novartis AG, reported successful scale-up of manufacture of a new group B meningococcal vaccine, MeNZB, developed initially for New Zea-land, which has experienced a group B disease epidemic for 13 years. No other vaccine was on the market to protect against this specific strain. Since 1991, over 5,300 New Zea-landers had been infected, and over 200 had died and many more were left disabled. A nationwide vaccination program with MeNZB was expected to start in mid-2004. Chiron is also developing a recombinant type B vaccine MeNZB received approval in New Zealand on July 7, 2004. If successful in New Zealand, Chiron plans to market the vaccine worldwide. Chiron merged into Novartis AG in spring 2006. In Aug. 2006, Novartis reported that New Zealand studies showed MeNZB has an 80% efficacy rate in preventing cases of meningococcal B disease. A staggered roll-out of the vaccine in New Zealand targeted highest-risk populations first, such as indigenous Maori and Pacific communities in the country’s northern region, and reduced cases of the epidemic strain in these groups by 90% and 70%, respectively, over the campaign. The three-dose vaccination campaign reached about one million people, from infants to age 20.

In Feb. 2008, the Serum Institute of India and the U.K. Health Protection Agency (HPA) formed a collaboration to develop a vaccine for the prevention of meningococcal septicaemia and meningitis. The firms hope the new vaccine will be effective against all forms of the disease. The HPA has been developing a vaccine against Group B meningococcus for over a decade. The candidate vaccine is currently in early trials in the U.K. and contains an organism known as Neisseria lactamica, which is similar to N. meningitidis. The vaccine will be manufactured and undergo clinical testing in India.

Wyeth is developing a meningococcal conjugates vaccine. In Dec. 2006, Wyeth granted a contract to Crucell N.V. (formerly Berna Biotech Ltd.) for its manufacture.

In Aug. 2004, the Serum Institute of India signed an agreement with the international Meningitis Vaccine Project (MVP), World Health Organisation (WHO), and the international charity PATH (Program for appropriate Technology in Health). for development of a conjugate meningitis vaccine A (Men A), based on vaccine technology licensed from the Food and Drug Administration (FDA). The vaccine is expected to be able to be administered to infants, unlike current vaccines that can only be given to children two years old and over, and is may provide protection for 10 years vs. 3 years for most current meningitis vaccines. Group A polysaccharides for conjugate manufacture are being supplied by SynCo Bio Partners (Amsterdam, The Netherlands) The Serum Institute plans to manufacture 25 millions doses/year at a cost as low as $ 0.40 cents per dose for use primarily in Africa. Supported primarily by a $70 million grant from the Bill & Melinda Gates Foundation, MVP formed a partnership between the FDA, SynCo Bio Partners and Serum Institute of India. Men A is entering trials in Gambia and Mali in 2006.

GlaxoSmithKline (GSK) is developing multiple combinations of new meningitis conjugate vaccines to prevent infection against four of the five serogroups of N. meningitidis that cause bacterial meningitis: A, C, W and Y. GSK’s multiple combinations — Hib-MenCY, Hib-MenC (Menitorix), MenACWY, and Hib-MenAC-DTPw-HB - are specifically tailored to meet the medical and age-related needs of various geographical areas worldwide.

Transgene Biotek (Hyderabad, India) has developed a miningococcal A, C, Y &W-135 vaccine in collaboration with JN International Medical Corp. (NE, USA). This is targeted for use in lesser-developed countries, with purchases by international public health programs, e.g., WHO. The vaccine is expected to cost about $1.50-$2.00/dose in bulk. Trangene is also developing a miningoccal serogroup B conjugate vaccine to add to this vaccine.

In May 2006, VaxGen and EndoBiologics International Corp. entered into a collaboration for development of a miningococcal serogroup B vaccine.

In Dec. 2006, BioVeris Corp. (Gaithersburg, MD) concluded a licensing agreement with Baxter Healthcare for its Neisseria meningitidis group C vaccine to be used as a component in new combination vaccine expected to be used as a single inoculation.

In Jan. 2007, The Serum Institute of India and the Health Protection Agency (HPA), U.K., formed a colla-boration for development of a vaccine for the prevention of meningococcal septicaemia and meningitis, including all forms of meningococcal disease. The HPA has been working on a vaccine against Group B meningococcus, containing Neisseria lactamica, for a decade. This is in Phase I testing in the U.K. The HPA licensed its vaccine technology to the Serum Institute, which will combine this Group B vaccine with the components of the Group A and C conjugate vaccines it already manufactures and conjugates for the Y and W135 strains. The new vaccine will be manufactured and undergo clinical trials in India.