Status: approved in EU in March 2009

Organizations involved:

GlaxoSmithKline Biologicals S.A. (GSK) – Manuf.; R&D; Tech.; Intl. mark.

GlaxoSmithKline plc – Parent

Cross ref: See the Pneumococcal Vaccines entry (#512). See the entry above for Prevnar, against which this vaccine will compete.

Description: Synflorix is a formulation of Pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV), a decavalent (10-antigen-containing) vaccine composed of partially hydrolyzed capsular (outer coat) polysaccharide and oligosaccharide antigens from ten Streptococcus pneumoniae bacteria serotypes (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F) individually cultured, purified, with 8 of the antigens chemically conjugated to Haemophilus influenzae protein D from a non-typeable strain of H. influenzae, one conjugated to a Diphtheria toxoid carrier protein and another conjugated to a Clostridium tetani (tetanus) toxoid carrier protein.

The H. influenzae protein D carrier is, itself, antigenic. Streptorix is the first vaccine to provide protection against non-encapsulated H. influenzae. The 10-valent vaccine is designed to protect children against both invasive pneumococcal disease (IPD) and bacterial respiratory infections such as acute middle ear infections (otitis media). The vaccine contains the seven S. pneumoniae serotype antigens in Prevnar, plus serotypes 1, 5 and 7F, which have been associated with severe pneumococcal disease in children younger than 5 years of age. The 10 S. pneumoniae serotypes in the candidate vaccine account for over 80 % of paediatric invasive pneumococcal disease worldwide.

Biological.: The protein D carrier molecule conjugated to the antigens is a H. influenzae 42 kDa surface, exposed, highly-conserved lipoprotein with antigenic activity expressed in all non-typable H. influenzae (NTHI and other encapsulated) strains. Protein D is considered a virulence factor, associated with bacterial ciliary beating and is an important pathogenicity factor in otitis media (H. influenzae ear infection).

Non-typeable H. influenzae (NTHI) are an important cause of ear infections in young children and may be involved in other serious infections like pneumonia and ear infections due to non-typeable H. influenzae.

Streptorix was an earlier, 11-antigen (11-valent), “prototype” version of Synflorix, apparently containing slightly different conjugate antigens. Streptorix entered trials in 1998.

Nomenclature: Pneumococcal Vaccine-HiD [BIO]; Synflorix [TR]; Streptorix [TR former]; Pneumococcal non-typeable Haemophilus influenzae Protein D conjugate candidate vaccine (PHiD-CV) [SY]; Streptococcus pnuemoniae capsular antigens--Haemophilus influenzae protein D conjugates vaccine [SY]

Companies.: Synflorix (and earlier Streptorix) was developed and will be manufactured and marketed internationally by GlaxoSmithKline S.A.

Status: On Jan. 31, 2008, the EMEA/European Union (EU) accepted the MAA filing from GSK seeking approval of Synflorix. Various other international applications were filed in parallel and will continue to be filed. There is as yet no discussion about a U.S. filing.

GSK has filed with the World Health Organization (WHO) for prequalification (PQ), a service provided by the WHO to facilitate access to medicines in less-affluent countries. A WHO prequalification, essentially an approval by WHO, will facilitate rapid access by developing world countries once the candidate vaccine is approved in Europe (with many or most lesser-developed countries and many private and public health program funding organizations preferring to use vaccines that have been approved by relatively strict regulatory agencies in major market countries). The WHO policy is that pneumococcal conjugate vaccines should be a priority for inclusion in national childhood immunization programs worldwide.

On March 31, 2009, Synflorix received European Unio (EU) approval. Synflorix is indicated for active immunisation against invasive disease and acute otitis media (AOM) caused by Streptococcus pneumoniae in infants and children from six weeks up to two years of age; invasive pneumococcal diseases (IPD) caused by S. pneumoniae include meningitis, bacteraemia (blood infections); and bacteraemic pneumonia.

The vaccine (in spring 2009) is also approved in Canada for immunization of infants and children (six weeks up totwo years) against 10 S. pneumoniae serotypes and invasive disease caused by these serotypes (received approval on Dec. 11, 2008). It received approval in Australia (March 25, 2009) for immunization of infants and children (six weeks up to two years) against 10 S. pneumoniae serotypes in a broader range of infections caused by these serotypes, including invasive disease, pneumonia, and AOM. Licensure is also in advanced stages of regulatory approval in many countries across the world.

Medical: Synflorix is administered in three doses during the first year of life, and stimulates immunity to 10 capsular serotypes of S. pneumoniae

Synflorix provides protection against the 10 most important pneumococcal serotypes worldwide, including three serotypes (1, 5, 7F) not contained in Prevnar. These three additional serotypes seem to be particularly associated with severe disease and hospitalisation. The 10 types covered by Streptorix represent about 80% of circulating invasive S. pneumoniae serotypes worldwide. Synflorix offers protection against S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, plus three serotypes (1, 5, 7F) that have been associated with severe pneumococcal disease and increased hospitalization rates in children aged less than five years, Prevnar does not contain certain pnuemococcal serotypes that are prevalent in the fast-growing markets of Southeast Asia (serotypes 1 and 5).

There is no evidence yet that this vaccine prevents meningitis or pneumonia due to H. influenzae type B (Hib) and it is unlikely to provide protection against typeable strains of H. influenzae, so Hib vaccination is still essential. Overall, by protecting against AOM caused by both S. pneumoniae and H. influenzae, Synflorix may significantly decrease the burden of AOM worldwide and lead to a significant reduction in related doctor visits and antibiotic prescriptions. This benefit is in addition to reducing invasive pneumococcal disease

Trials: In its trials, a high level of protection has been seen against acute otitis media (AOM) caused by pneumococcal serotypes, similar to that with Prevnar. In addition, significant protection was observed against AOM caused by H. influenzae. Antibody responses for all co-administered vaccines have shown that Synflorix does not interfere with co-administered paediatric vaccines.

The EU application is based on the results from POET (Pneumococcal Otitis Efficacy Trial; which used the earlier Streptorix version of Synflorix). This was a randomized, double-blind, placebo-controlled study conducted in more than 4,900 children in the Czech Republic/Slovakia. Children vaccinated with three doses of Synflorix plus a booster and followed-up for ~2 years demonstrated 58% efficacy against vaccine serotype acute otitis media (AOM); 52% efficacy against any pneumococcal AOM; 36% efficacy against NTHI-related AOM; and 34% efficacy against any clinical AOM. Compared to Prevnar, Synflorix elicited comparable (to Prevnar) biologically active antibody responses for each of the 7 S. pneumoniae serotypes common between the GSK candidate vaccine and the currently available Prevnar 7-valent pediatric pneumococcal conjugate vaccine. Depending on serotype, at least 87.3% and up to 100% of subjects studied reached the antibody response threshold in the candidate vaccine group. For the three additional serotypes contained only in the candidate vaccine, at least 93.1% of subjects studied reached the antibody response threshold. Depending on the relative importance of serotypes 1, 5 and 7F in a respective region or country of the world, Synflorix was concluded to have the potential to prevent more invasive pneumococcal disease than the 7-valent vaccine (Prevnar)

Although the seven pneumococcal serotypes covered by Prevnar are useful in the U.S., Prevnar is not effective against many strains that are prevalent in the developing world. Synflorix provides coverage for more than 80% of pediatric infectious pulmonary diseases worldwide, and could be a major step in reducing the impact of diseases caused by infection from S. pneumoniae and NTHI. Although a study in the NEJM (2001:344;403-409) attempted to address the potential benefit of Prevnar, the data showed that the vaccine only protected 6% of vaccinated children against AOM and resulted in increased infection rates from other pneumococcal serotypes not included in the vaccine. Also, in October 2007, University of Rochester researchers discovered that a serotype 19A pneumococcal strain was resistant to all U.S.-approved pediatric antibiotics was able to cause AOM in children already vaccinated with Prevnar.

Disease: Synflorix will be largely differentiated from Prevnar by its additional efficacy against otitits media due to S. pneumonia and non-typeable H. influenzae. The burden of otitis media worldwide is significant. It is one of the most frequent childhood diseases, is the most common reason in the U.S. for physician visits in children under 3 years of age and is the most frequent indication for prescription of antibiotics. The pathogens, S. pneumoniae and NTHi, are recognized as the two leading causes of acute bacterial otitis media, each accounting for up to 40 % of cases in

children. Until Synflorix, no vaccine has offered protection against NTHi infection.

Disease caused specifically by Haemophilus influenzae type b (a typeable strain of H. influenzae) is already addressed by existing conjugate vaccines (see Prevnar and other pneumococcal vaccine entries). The “non-encapsulated” or “non-typeable” Haemophilus influenzae (NTHi) strains are also a leading cause of bacterial respiratory infections, yet currently are not vaccine preventable.

The three additional pneumococcal strains – 1, 5 and 7F – in Synflorix but not Prevnar cause a significant number of severe childhood invasive diseases, accounting for 5-25% of all cases in different regions of the world and are an increasingly prominent cause of serious disease in Europe.

The increasing prevalence of antibiotic resistant S. pneumoniae and and non-typeable H. influenzae are making prevention by vaccines more important. Bacterial respiratory diseases are commonly treated with antibiotics. However, in some countries antibiotic resistance has been gradually increasing among S. pneumoniae and NTHi in recent years This resistance makes treatment difficult and results in longer hospitalizations and more expensive alternative therapy.

Market: First-half 2013 sales were $274 million, with 2012 sales estimated at about $550 million.

The expanded coverage of Synflorix, compared to Prevnar, with three additional S. pneumoniae antigens, and the HiB carrier protein providing protection against non-typeable H. influenza strains, will provide advantages in the market compared to Prevnar, which had $2.4 billion sales in 2007 (about half of this in the U.S.). However, GSK has not disclosed plans for seeking Synflorix approval in the U.S., so Prevnar will remain dominant in this market (and a next-generation form of Prevnar with 13 antigens, with EU and other filings expected in 2009).

Much of the market and market uptake for Synflorix will depend on its displacement of Prevnar in various countries public health immunization programs (much of which may depend on how the organizations the provide most of the funding for these programs perceive the cost-benefits of Synflorix vs. Prevnar). It will be a difficult choice between NTHi coverage offered by Synflorix and extra pneumococcal serotypes offered by Prevnar.