OPTAFLU, a new flu vaccine, was licensed by EMEA, the European Medicines Authority, last summer. However, licensed vaccine for the current season's strains is still lacking. Released batches are not available. Nevertheless, the manufacturer Novartis is already advertising "OPTAFLU 2007/08" (1).

Unlike traditional virus cultures on incubated hens' eggs, the vaccine viruses for OPTAFLU are replicated in a permanent (immortal) cell line. Use of the MDCK* cell line produced by MADIN and DARBY in 1958 from the kidneys of a cocker spaniel is intended to make vaccine production more flexible and independent of hens' eggs and to increase the yield. This is regarded as an advantage especially in the case of a flu epidemic (2). The company is thus entering new territory. The MDCK cells are a tumorigenic cell line, that is, the cells can develop tumours in a host organism. The fewer cells are required for this in an animal experiment, the greater is the carcinogenicity. Ten of the MDCK cells used to manufacture OPTAFLU are sufficient to progress to tumours in naked mice. They are therefore regarded as highly tumorigenic. Tumorigenic cell lines are indeed used today for the production of biologicals such as monoclonal antibodies but not so far for vaccines that are on the market (3). According to the EMEA's assessment, there are no safety concerns, partly because only intact cells are tumorigenic or oncogenic in tests with rodents, but not cell lysates or DNA. Intact cells are regarded as completely eliminated from the vaccine by the manufacturing process (2). However, serveral members of the advisory committee of the American FDA expressed concern in late 2005, e.g. because of the potential oncogenicity of DNA from MDCK cells, which remains in the end-product in small amounts (< 10 ng/0.5 ml) (3). In the USA the vaccine has not so far been licensed.

CLINICAL EFFICACY: The EU licence is based on three phase III studies, not yet published in full, comparing OPTAFLU with a conventional flu vaccine from the same manufacturer in the 2004/05 and 2005/06 flu season (AGRIPPAL, not on the market in Germany), in which over 3,800 adults aged at least 18 years took part. The exclusion criteria included serious diseases and egg allergy. The studies were designed to test the immunogenicity. OPTAFLU works similarly to the egg-based vaccine. Antibody titres that are regarded as protective (at least 1:40 in the haemagglutination inhibition test) were obtained in the main study in 76% to 98% of the subjects who received OPTAFLU and in 74% to 98% in the control group (2).

ADVERSE EFFECTS: The range of side effects of OPTAFLU appears in licensing studies to correspond essentially to that of the conventional vaccine. However, comprehensible comparative data on incidence are largely lacking in the European assessment report. The most common local reactions with both vaccines were pain and erythema (6% to 18%), with pain at the injection site more common with OPTAFLU, and the most common systemic reactions were headache, fatigue and malaise (9% to 13%). Gastrointestinal disorders were noticeably common (2).

Data from an extension study in which the participants were randomised again in the second year indicate increased reactogenicity of the new vaccine: local and systemic reactions were more common overall in the second year in the group that was first immunised with the egg-based vaccine and then with OPTAFLU than in the other groups. Severe systemic reactions were again observed only in study participants who received OPTAFLU twice in succession (2).

Pain in the injection region and serious systemic reactions on repeat immunisation are among the risks for which the EMEA plans special post-marketing surveillance (2). The European authority obviously does not plan a long-term surveillance of vaccinated persons as suggested by FDA advisors (3) in 2005 because of the at least theoretical risk of damage by the tumorigenic cell line used for the manufacturing process.

COSTS: The vaccine, which is so far not licensed for the current season would be about 10% to 30% dearer on market introduction compared with conventional vaccines (27.48 for one, 178.07 for ten prefilled syringes).

	There are so far no released batches of the flu vaccine OPTAFLU licensed in summer 2007. Nevertheless, it is already being advertised for the current season.
	Unlike conventional flu vaccines, OPTAFLU is manufactured on the basis of a permanent cell line that is highly tumorigenic in animal experiments.
	Efficacy advantages of the new vaccine compared with an egg-based vaccine are not proven.
	The range of side effects is similar compared with a conventional vaccine but OPTAFLU produces pain at the injection site more frequently. The risk of severe systemic reactions is possibly increased on repeat vaccination with OPTAFLU.
	Whether use of a highly tumorigenic cell line for the production of OPTAFLU involves a risk for users, e.g. in the form of an increased cancer risk, cannot, in our opinion, be finally assessed at present.
	The fact that OPTAFLU production is independent of the availability of hens' eggs may be useful in the event of a pandemic. For seasonal flu prophylaxis, we currently see no indication for the innovation in view of the injury potential, which cannot be conclusively assessed.
	Because of reservations regarding safety and because of the fact that the vaccine was not even tested in patients with severe hen's egg allergy, the majority of the editorial board expressed reservations regarding the use of OPTAFLU even for persons in whom conventional flu vaccines are contraindicated.
	In order to obtain better answers at least in the future to all the unanswered safety questions, it must be demanded that as far as possible all who obtain the vaccine for any reason are followed up long-term and systematically.

1

Novartis: advertisement for OPTAFLU, Ärzte Ztg. [Medical Newspaper] of 30 Nov./1 Dec. 2007

2

EMEA: European Assessment Report (EPAR) OPTAFLU, issued 1 Aug. 2007; available at: http://www.emea.europa.eu/htms/human/epar/o.htm

3

Committee Discussion: Meeting of the Vaccines and Related Biological Products Advisory Committee, 16. Nov. 2005; http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4188t1.pdf

*

MDCK = Madin Darby Canine Kidney