menveo :: Article CreatorGSK Trails After Pfizer In 5-in-1 Meningococcal Vaccine Race
The FDA has started a review of GSK's five-in-one meningococcal vaccine, cueing up a decision in mid-February next year, as it tries to chase down a rival candidate from Pfizer cleared last year.
The new vaccine is a combination of GSK's already-approved vaccines Bexsero and Menveo and is designed to protect against meningitis and blood poisoning caused by the A, B, C, W, and Y serogroups (MenABCWY) of the bacteria Neisseria meningitidis.
MenABCWY covers five of the six serogroups that cause most disease worldwide, with the B, C, and Y strains responsible for most cases of invasive meningococcal disease (IMD) encountered in the US.
GSK is currently the market leader in the meningococcal vaccine market, racking up sales of £1.26 billion (almost $1.6 billion) last year across the Bexsero and Menveo brands, but is having to play catch-up to Pfizer in the MenABCWY combination category after the FDA cleared the latter's Penbraya in October.
Penbraya also combines elements from Pfizer's meningococcal vaccines Trumenba and Nimenrix, which together made around $300 million in 2023, and started shipping in the US earlier this year.
Also active in the category is Sanofi, which sells MenACWY vaccines Menactra and MenQuadfi, lacking coverage of the B serogroup considered the most common cause of meningococcal disease in the US. Sanofi is working on a MenABCWY shot codenamed SP0230, which is currently in mid-stage clinical development.
The companies see potential for their new vaccines in simplifying immunisation schedules and reducing the number of injections needed – four across two products before Penbraya's launch – as well as potentially enhancing uptake and reducing costs.
They argue that the current need to use multiple meningococcal vaccines to provide coverage across all meningococcal strains has resulted in confusion among consumers and doctors, leading to poor compliance and restricting sales.
In the US, while meningococcal vaccine recommendations for all five serogroups have been in place since 2015, annual immunisation rates for IMD have remained low overall.
With the FDA review now underway, GSK is hoping for a positive verdict for its shot by the action date of 14th February.
"IMD is an unpredictable but serious illness that can cause life-threatening complications," said GSK in a statement. "Despite treatment, among those who contract IMD one in six will die, sometimes in as little as 24 hours. One in five survivors may suffer long-term consequences such as brain damage, amputations, hearing loss, and nervous system problems."
Meningococcal Group A, C, Y And W-135 Conjugate Vaccine
Meningitis — acute infection of the membranes that surround the brain and spinal cord — can be fatal within hours, and can result in serious sequelae such as deafness in up to a third of survivors1,2. The application of effective polysaccharide–protein conjugate vaccines has dramatically reduced the incidence of bacterial meningitis caused by Haemophilus influenzae type b and Streptococcus pneumoniae, both through direct and herd immunity effects, illustrating the value of disease prevention with conjugate vaccines1,2. The Gram-negative bacterium Neisseria meningitidis is another important cause of bacterial meningitis and other invasive bacterial infections, and so has been a focus of substantial efforts for further vaccine development2.
Basis of discovery
Pathogenic strains of N. Meningitidis possess a polysaccharide capsule that serves as a major virulence factor2. Five pathogenic strains — serogroups A, B, C, Y and W-135, determined by the composition of the polysaccharide — are common causes of invasive bacterial infections, and the polysaccharides of these strains have been targeted for vaccine development2. Serogroup B polysaccharide is not suitable for vaccine development, however, owing to its poor immunogenicity and immunological cross-reactivity with human neural antigens2.
The first meningococcal vaccine licensed in the United States — MPSV4 (Menomune; Sanofi Pasteur), which was approved in 1981 — is based on polysaccharides from serogroups A, C, Y and W-135 (Ref. 2). However, as with polysaccharide vaccines in general, it has important limitations, including lack of induction of immunological memory, relatively short duration of protection and lack of immunogenicity in infants.
To improve the immunological response, conjugate vaccines in which meningococcal polysaccharides are covalently linked to a carrier protein have been developed. In 2005, the quadrivalent meningococcal vaccine MCV4 (Menactra; Sanofi Pasteur) — which contains N. Meningitidis serogroup A, C, Y and W-135 polysaccharides conjugated individually to diphtheria toxoid — became the first such product to be approved in the United States. It has now been joined by a second such product, MenACWY–CRM (Menveo; Novartis Vaccines and Diagnostics), in which meningococcal oligosaccharides are covalently linked to diphtheria cross-reactive material (CRM197).
Vaccine properties
Menveo contains N. Meningitidis serogroup A, C, Y and W-135 oligosaccharides conjugated individually to Corynebacterium diphtheriae CRM197 protein3,4. Polysaccharides are purified from bacterial fermentations of the respective N. Meningitidis strains, and CRM197 is purified from fermentations of C. Diphtheriae4. Oligosaccharides are prepared for conjugation from purified polysaccharides by hydrolysis, sizing and reductive amination, and then covalently linked to the CRM197 protein3,4. The resulting glycoconjugates are purified to yield the four vaccine components4. Each dose of vaccine contains 10 μg serogroup A oligosaccharide, 5 μg each of serogroups C, Y and W-135 oligosaccharides, and 32.7–64.1 μg of CRM197 (Ref. 4).
Clinical data
The immunogenicity of Menveo (administered by intramuscular injection) in subjects aged 11–55 years was investigated in a randomized controlled trial in which the serum bactericidal antibody responses were compared to those of Menactra4. The trial was conducted in 3,539 adolescents (11–18 years of age) and adults (19–55 years of age) in the United States, who were randomized to receive a dose of Menveo (n = 2,663) or Menactra (n = 876)4.
Sera were obtained from participants before vaccination and 28 days after vaccination, and serogroup-specific anticapsular antibodies with bactericidal activity were measured using pooled human serum that lacked bactericidal activity as the source of exogenous complement (hSBA)4. The primary immunogenicity end points were hSBA serological response rates to each serogroup 28 days after vaccination4. Serological response was defined as a post-vaccination titre of ≥1:8 for subjects with a pre-vaccination hSBA titre of <1:4, and a post-vaccination titre at least fourfold higher than baseline for subjects with a pre-vaccination hSBA titre of ≥1:4 (Ref. 4).
Non-inferiority of Menveo to Menactra in adolescents (aged 11–18 years) was demonstrated for all four serogroups based on the primary end point of hSBA serological response4. Non-inferiority of Menveo to Menactra in adults (aged 19–55 years) was also demonstrated for all four serogroups4.
Concomitant administration of Menveo and other vaccines recommended for adolescents was assessed in another trial involving 1,620 subjects aged 11–18 years4,5. Participants were randomized to three groups (1:1:1) to receive Menveo concomitantly or sequentially with combined tetanus, reduced diphtheria and acellular pertussis (Tdap) vaccine (Boostrix; GlaxoSmithKline) and quadrivalent human papilloma virus (HPV) vaccine (Gardasil; Merck)5. The hSBA serological response, and antibodies to Tdap antigens and HPV virus-like particles were determined before vaccination and 1 month after vaccination5.
The proportions of subjects with hSBA titres ≥1:8 for the four meningococcal serogroups A, C, Y and W-135 were non-inferior for both concomitant and sequential administration5. The immune responses to Tdap and HPV antigens were comparable when these vaccines were given alone or concomitantly with Menveo, and concomitant or sequential administration did not increase reactogenicity5.
Indications
Menveo is approved by the FDA for active immunization to prevent invasive meningococcal disease caused by N. Meningitidis serogroups A, C, Y and W-135 in people 11–55 years of age4.
Analysismeningococcal vaccines
Analysing issues for meningococcal vaccines is Lee H. Harrison, M.D., Professor of Medicine and Epidemiology at the University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
N. Meningitidis is a major cause of bacterial meningitis and other serious infections worldwide6. To prevent infection, quadrivalent meningococcal conjugate vaccine is recommended for all adolescents aged 11–18 years old and other high-risk people7. Menveo has recently become the second such vaccine to be licensed in the United States — currently for people aged 11–55 years — providing an alternative option to Menactra, which is currently licensed for people aged 2–55 years7, and might eventually be licensed for children as young as 9 months old.
Menveo is novel because it both covers four (A,C,W-135,Y) of the five major meningococcal serogroups and is immunogenic and safe when given as a four-dose schedule starting at 2 months of age8. This supports the ultimate plan to also obtain licensing approval for infants. Efficacy in infants is important because this group has the highest risk of developing meningococcal disease. Indeed, serogroup C meningococcal conjugate vaccines have been used with great success for more than a decade in infants in the United Kingdom and elsewhere.
There has also been other recent progress in meningococcal vaccine development. A conjugate vaccine that combines protection of infants against H. Influenzae type b and meningococcal serogroups C and Y is in late-stage development9. Ideally, meningococcal vaccines should cover as many clinically important serogroups as possible. However, serogroup A disease rarely occurs in the United States and serogroup W-135 currently accounts for a small proportion of infections in infants. A serogroup A conjugate vaccine for the prevention of meningococcal disease in the African meningitis belt (covering an area from Senegal to Ethiopia) will probably be available soon10, which is exciting because this region suffers from periodic, devastating meningococcal epidemics. Finally, there has been considerable progress in the development of broadly protective serogroup B meningococcal vaccines11,12, which are urgently needed because a substantial proportion of meningococcal disease in many parts of the world is caused by serogroup B strains6.
One of the striking features of meningococcal epidemiology in general is that it is highly dynamic, which makes formulation of an immunization policy for this disease akin to trying to hit a moving target. In the United States, rates of meningococcal disease have declined by more than 60%, to historically low levels13. Whether the decline in meningococcal disease incidence is part of the usual cyclical nature of meningococcal disease or represents a sustained change in the epidemiology remains to be seen. Based in part on the low incidence and that the majority of infant disease is caused by serogroup B strains, the US Advisory Committee on Immunization Practices is currently considering not recommending routine meningococcal immunization of infants.Boxed-text
Overall, with the recent licensure of Menveo, and other vaccines in the pipeline, the prospects for comprehensive vaccine prevention of meningococcal disease have never looked better. How Menveo and other meningococcal vaccines are ultimately utilized will depend on serogroup-specific measurements of disease burden, considerations of cost-effectiveness and programme implementation issues.
Box 1The market for meningococcal vaccines
Analysing the market for meningococcal vaccines is Nitin Mohan, IMS Health Americas, Canada.
The global market for meningococcal vaccines was valued at more than US$700 million in 2009 (Ref. 14). The current leading product is the quadrivalent conjugate vaccine Menactra (Sanofi Pasteur), which had sales of 446 million euros ($593 million) in 2009 (Ref. 14). Menactra is approved and sold solely in the United States and Canada. It has now been joined by Menveo (Novartis Vaccines and Diagnostics), which was approved by the US FDA in February 2010, and has also became the first quadrivalent conjugate vaccine available in Europe following its marketing approval in March 2010. However, the European market for quadrivalent vaccines is substantially smaller than in the United States given the different distribution of meningococcal serogroups and the availability of a vaccine for serogroup C. Serogroup B is the largest prevailing serogroup in Europe, but no broadly protective vaccines for this serogroup are currently available. Both Novartis and Pfizer have serogroup B vaccines in development.
Globally, infants are at the highest risk of infection with meningococcal disease, and so vaccines that can be administered to infants are desirable, and represent the largest potential market. Menveo was originally anticipated to be approved for use in infants by 2010, but the FDA has requested an additional 1,500-patient safety study prior to filing for this indication, which is anticipated to occur in 2011. The ability to give Menveo as part of the routine infant vaccination schedule starting at 2 months of age could be a significant advantage over Menactra. According to analysts, annual sales of Menveo are anticipated to be more than $550 million by 2013, following successful approval in the infant indication, and could increase to more than $1.5 billion by 2015 (Refs 15, 16).
GSK Chases Down Pfizer In 5-in-1 Meningitis Jab Contest
Armed with new data, GSK is preparing to file for approval of its new-generation meningitis vaccine, as it tries to maintain its leadership in the category against a challenge from Pfizer.
Preliminary results from a phase 3 study of the MenABCWY vaccine – which covers all five meningococcal strains in one go as an alternative to separate vaccinations – showed that it was at least as effective as vaccination with GSK's current MenB jab Bexsero and Menveo for MenACWY given separately.
Endpoints in the study included antibody titres against the various meningococcal strains, and the ability for sera taken from subject to kill Neisseria meningitidis bacteria in the lab. The data was presented at the European Society for Paediatric Infectious Diseases (ESPID) congress in Lisbon, Portugal.
The trial involved subjects aged 10 to 25 who received the vaccine as two doses given six months apart, and also found that the shot was generally well tolerated, with a safety profile consistent with Bexsero and Menveo.
GSK's chief scientific officer, Tony Wood, said that the results show the vaccine protects against "the broadest panel of circulating MenB strains to date," adding that MenB is "the most common cause of meningococcal disease in the US, with the lowest immunisation rate."
The drugmaker said it is now "working closely" with regulatory agencies to look at the data and prepare filings, without giving a timeline for that to happen. At the same time, the results from the trial will be used as a confirmatory study to seek a full license for Bexsero, which was given accelerated approval by the FDA in 2015.
In the meantime, however, GSK is lagging behind Pfizer, which filed for approval of its five-in-one meningococcal vaccine for the same target age group last December and is expecting to hear back from the FDA in October.
Pfizer's vaccine combines its Nimenrix for MenB and Trumenba for MenACWY, showing equivalence to the separate shots in phase 3 results reported last year.
Both companies see potential for their new vaccines in simplifying immunisation schedules and reducing the number of injections needed, as well as potentially enhancing uptake and reducing costs.
They argue that the current need to use multiple meningococcal vaccines to provide coverage across all meningococcal strains has resulted in confusion among consumers and doctors, leading to poor compliance and low sales.
That hasn't stopped Bexsero's steady growth, with sales approaching the $1 billion threshold last year, while Menveo added another $430 million.
Pfizer has been something of an also-ran in the market to date, with Nirmenrix making $193 million last year and Trumenba revenues not large enough to be broken out in its financial reporting. It is hoping to make up the ground with the new vaccine, if approved.
GSK's strong position in the category could be in its favour, however, and particularly the dominance of Bexsero, which has been something of a pathfinder shot for MenB around the world. The company has previously suggested that the 5-in-1 vaccine could eventually become a $1 billion to $2 billion product.
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