Menactra Overview for WYETH

Contracted by Script Medical Publishing Inc.
December 2006
By Kristin Jenkins

WINNIPEG — Menactra, the only conjugate vaccine offering protection against all four vaccine-preventable serogroups— A, C Y and W-135. [1] [product monograph, p. 1] —  is now indicated for active immunization against Neisseria meningitides in Canadians 2 to 55 years of age. [1] [product monograph, p. 5]

Although the duration of protection against invasive meningococcal disease remains unknown, trials in children aged 2-3 years show persistent immune response out to three years following immunization. Further, Menactra has demonstrated immune response and tolerability in 98-100% of children 2-4 years old previously vaccinated with monovalent conjugate meningococcal Group C (Men C) vaccine.

This polysaccharide diphtheria toxoid vaccine is not indicated for the prevention of invasive meningococcal disease (IMD) caused by serogroup B, which is not vaccine preventable. Trials in adolescents aged 11-18 years of age, however, have revealed a robust immune response for all four vaccine-preventable serogroups. (3) In children 2-10 years of age, Menactra demonstrated a high immune response at six months.

“The prevention of meningococcal infections poses multiple challenges for most vaccinologists,” Dr. David Scheifele told physicians attending a recent satellite symposium here on the prevention and control of meningococcal disease. Dr. Scheifele is director of the Vaccine Evaluation Center, Vancouver, and CIHR/Wyeth chair in vaccine research at the University of British Columbia.

While IMD is rare, risk persists throughout life with peaks during infancy, adolescence and in old age (TK). The existence of multiple serogroups, which vary in prominence over time as well as by geographic region and age group, further complicates the clinical picture by creating “a moving target,” said Dr. Sheifele.

Statistics from the 2002-2003 Immunization Program Active Study [source: Canada Communicable Disease Report (CCDR) 2006; 32:97-106], which includes more than 50% of the population, shows that four Canadians are infected with IMD each week. Every two weeks, there is one fatality nationwide.

“When we look across the country,” said Dr. Scheifele, “we see that the mortality associated with IMD is not so rare.” Complicating matters is the fact that death commonly occurs within 24-48 hours of onset of symptoms.  And while the overall mortality rate is 10%, meningococcemia—the most aggressive form of the disease, has a case fatality rate of 20%-40%.[1] [product monograph, p. 35]

Those who survive IMD experience must contend with devastating morbidity. Neurological sequelae such as hearing loss, speech disorders, brain damage, seizures and paralysis, as well as loss of limbs, lung damage and psychological disorders affect up to one in five survivors. [1]  “Residual morbidity in survivors is significant,” said Dr. Scheifele, adding that “we may be under-appreciating the true morbidity associated with this disease.” 

In one U.S. report by Kaplan S et al (Pediatrics 2006; 118:e979) sequelae in 146 surviving children included amputation of all four extremities (1), skin necrosis (14), skin grafts (4), seizures (9), deafness (14), ataxia (4) and hemiplegia (3).

Similarly, data out of the U.K. (Booy, R et al) reveal the lingering impact of IMD in a group of 101 survivors 15-19 years of age with matched controls assessed at 18-36 months following group C illness. Some 57% had major physical sequelae, mainly fatigue (p=0.04), and 28% had vascular problems resembling Raynaud’s disease. Inability to concentrate, irritability and insomnia resulted in reduced school performance and mental function (p=0.07), and reduced quality of life (p=0.01). Only 53 survivors had medical followup of any kind, noted Dr. Sheifele.

Clinical studies indicate Menactra has an excellent safety profile and is generally well-tolerated in children, adolescents and adults. [1]

The most commonly reported soliticited adverse reaction in children (2 to 10 years of age) was pain at the injection site (40-48%), drowsiness (10-25%), irritability (11-35%) and diarrhea (12-16%). The most commonly reported solicited adverse reactions in adolescents and adults were local pain (55%), headache (37%) and fatigue (31%).[1]  

Group C disease appears to be the culprit behind most outbreaks in Canada, noted Dr. Sheifele, which tend to occur in 10-year cycles. Group Y disease, which used to be rare, has increased in prominence in both Canada and the U.S. since the early 1990s. “In 1990, it was a two-actor play featuring Group B and C disease,” said Dr. Sheifele. “Group Y disease was only cited in 2% of all cases.” Ten years later, the scene vis-à-vis dominant serotypes has changed. “We have a three-actor play with Group Y disease accounting for 34% of cases in the U.S. In 2005, Y decreased to 27% but it’s still a three-actor play,” noted Dr. Sheifele.

In 2001, Group C disease dominated the scene in Canada, but in 2003, Group Y disease also took on a bigger role in IMD. “The distribution of serogroups differs between children and adults,” pointed out Dr. Sheifele. A significant number of Y and W cases have been seen in children less than one year of age as well as in those 10-19 years of age.

“N. meningitidis is a very clever bug which transforms itself through acquisition of genes and horizontal gene transfer,” said Dr. Gregory Gilmet, medical team leader, global medical affairs, sanofi pastur, Swiftwater, PA. “Menactra is a broad spectrum meningococcal conjugate vaccine that provides individuals the potential for long-term protectioin,” he said. This is important from both an individual and a public health perspective, noted Dr. Gilmet. “From an individual perspective,” he told delegatve, “a quadrivalent meningococcal conjugate vaccine in Canada provides the highest risk reduction for IMD A, C, Y and W-135 and reassurance that “all is being done that can be done.”

From a public health perspective, Menactra can make a significant impact on meningococcal incidence in regions where Y and W-135 strain form a significant portion of IMD. The quadrivalent meningococcal conjugate vaccine also provides the greatest flexibility in disease prevention and control given the changing and unpredictable epidemiology of meningococcal disease. “With meningococcal disease,” Dr. Gilmet told delegates, “the past is no predictor of the future. Forecasting the epidemiology of meningococcal disease, he added, is like driving a car by looking in the review mirror.”

Target groups for Menactra in Canada in include children 2-10 years of age, the idea here being to broaden and boost protection. “Parents may be under the perception that children are protected because of the infant/toddler Men C program,” pointed out Dr. Gilmet.  Adolescents and young adults are a high-risk target group in Canada because  of the high proportion of serogroup Y cases that currently exists in teens.

Is broader protection better? asked Dr. Gilmet. Although Alberta is now following the Spain and NACI recommendation of routine vaccination for children at 2, 4, and 6 months, Dr. Gilmet noted that estimates of vaccine effectiveness show that viral antibody titers are almost undetectable after one year. In children older than two years of age, however, vaccine efficiency is “quite good” at 61-95%, he said. “The duration of immunity appears to be age dependent and six months of age appears to be a critical stage at which a booster dose may be necessary.”

Although just how long the vaccine remains effective is not currently know, “we are confident that the vaccine will provide protection in adolescents and adults for as long as eight year,” said Dr. Gilmet in response to a question from the audience during discussion period. “We will have five-year data very soon,” he added.

Vaccines don’t require a minimal interval for sequential doses, so Menactra can be given to a child who has received the Men C vaccine without waiting.

Key findings out of a U.S. multi-center, comparative clinical trial (**) to evaluate the immunogenicity and safety of Menactra protein conjugate versus Menomune polysaccharide, indicate that while the safety profiles of the two vaccines were similar, Menactra produced significantly higher seroconversion rates, defined as a four-fold increase in titer. In the study, 1,408 healthy two to 10 year-olds were randomized to receive either one i.m. dose of Menactra or one s.c. dose of Menomune.

By 28 days postvaccination, Menactra vaccine seroconverted in 86-99% of children who were initially seronegative for serogroups A,C, Y and W-135. By comparison, in children receiving Menomune vaccine, the seroconversion rates were 80-95%.

At 28 days postvaccination, Menactra produced significant higher serum bactericidal activity (SBA) geometric mean titers (GMTs) —a measure of immunogenicity directly relevant to protection from infection and the basis for licensure of Menactra— for all four serogroups than Menomune. At six months, antibodies persisted at significantly higher levels than Menomune, reported Dr. Gilmet. In addition, antibodies persisted at significantly higher levels than Menomune vaccine at six months.

Following this trial, subjects from the children study who were 2-3 years old at the time of primary conjugate vaccination were recruited 2-3 years later for a low-dose polysaccharide challenge***. Reponses were comparied to those of vaccine-naïve age-matched controls and both groups received a reduced dose of polysaccharide vaccine (1/10 a normal dose of Menomune) and subjects were then randomized to provide blood samples at eight or 28 days following the challenge dose.

In these young children, the SBA GMTs remain elevated for all four vaccine serogroups three years’ post vaccination, said Dr. Gilmet. “Robust boosting responses for all four vaccine serogroups consistent with memory induction were evident eight days post low dose polysaccharide challenge,” he noted.

In a multicenter, double blind, active control U.K. study of booster and primary response in 2-5-year old children primed with the Men C conjugate**** there was a consistently robust immune response in all children who received Menactra versus placebo, said Dr. Gilmet.

In the study, two-five year olds who were primed with a monovalent C vaccine in infancy were randomized to receive Menactra or control vaccine. The control group received Hib vaccine during a catch up campaign and blood was drawn at day 0 and 28.

The study showed that not only was Menactra effective in priming for A, Y and W-135 and “boosting” serogroup C in previous MenC recipients, but one dose primes for memory. Both immunological characteristics are expected of a conjugate vaccine, said Dr. Gilmet.

Much of the understanding of the underlying immunology of meningococcal serogroups has come out of seminal studies in U.S. army recruits stationed at Fort Dix, NJ. In a group of 14,000 recruits observed over an eight-week boot camp, 54 developed IMD. All 54 had serum bacteriocidal antibodies in a ratio of less than 1 to 4. As a result, noted Dr. Gilmet, it was learned that serum antibody titer levels of greater than or equal to 1 to 4 conferred immunity, at least over the short term, against the outbreak strain C. It did not confer protection against any of the other strains including B and Y.

In rabbit complement studies, which are readily accessible and can be standardized, there was a four-fold rise in serum antibody titers following vaccination. These studies looked at two kinds of vaccines: the older polysaccharide vaccines which have been available for 20 years and are excellent except that they don’t work in children younger than two years of age. Experience with other conjugate vaccines, including Hib vaccines and pneumovalent vaccines indicates that it should boost as well as reduce transmission or “carriage” -- an important property in conjugate vaccines.”

Animal studies also indicate that vaccination results in a 48-80% reduction in the incidence of IMD in the non-vaccinated population, conferring herd immunity. This protective effect is not durable, however, particularly in children younger than six months of age

** Pichichero M et al. Pediatr Infect Dis J. 2005;24:57-62

*** Pichichero M et al. Pediatr Infect Dis J. (in press)

****El Bashir H et al. Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine. Vaccine 2006 (24): 2544-2549

3. Keyserling H, Papa T et al.
Safety, imunogenicity and immune memory of a novel meningococcal (Groups A, C, Y and W-0135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med 2005; 159:907-13