Options for Live Attenuated Influenza Vaccines (LAIV) In the Control of Epidemic and Pandemic Influenza 12-13 June 2007
Summary and meeting documents
At the present time, if an influenza pandemic were to occur, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population, an estimated 6.7 billion. Following wide ranging stakeholder consultation, the Global Pandemic Influenza Action Plan (GAP) was launched in late 2006 to increase vaccine supply. According to the GAP document, one of the three main approaches to achieving this goal is to increase production capacity. In stepping up production capacity, several strategies have been identified . One of the most promising of these is the expansion of Live Attenuated Influenza Vaccine (LAIV) production.
In the wake of this consensus WHO convened representatives from national immunization programs, regulatory authorities, vaccine manufacturers and public health scientists on 12-13 June 2007 to analyze what could be considered the ‘untapped potential’ of LAIVs. The objective of the meeting was to summarize the state-of-the-art in both established seasonal and candidate pandemic LAIV vaccines and to recommend future research to explore the potential of LAIV in the control of epidemic and pandemic influenza. Alongside the objective of creating a reference point for further LAIV development, the meeting also represented a preliminary step in the update of the WHO guideline on LAIV vaccines, which is due in late 2008.
Despite more than 50 years positive experience of LAIV in Russia and, more recently, in the US, LAIV vaccines currently represent only a small fraction – less than 1 per cent – of global influenza vaccine production. Yet, the potential advantages of LAIV are considerable, in speed, scale and cost of production, as well as through the simplicity of its nasal route administration, in reducing healthcare worker needs. Increased indirect protection through herd immunity, particularly through LAIV vaccination of children, is another potential advantage, at least in seasonal vaccination settings.
While the upstream process for LAIVs during manufacture is the same as for inactivated vaccines, they require less complex downstream processing, making them more appropriate for technology transfer to enable vaccine production in developing countries – another key GAP strategy. LAIV vaccines have a lower unit cost and a higher production yield, estimated at least 10 times higher than for inactivated vaccines. Furthermore, the capital investment required for an egg-based LAIV production in an already established vaccine manufacturing campus is in the magnitude of less than US$10 million compared to US$ 100-200 millions for egg-based inactivated vaccines, not to mention the many hundreds of millions of dollars required for the establishment and regulatory approval of a cell culture substrate based influenza vaccine producing facility.
Regulatory and development status
Historically, five seasonal LAIV backbone strains reached regulatory approval status: A/Len/134/17/57, A/Len/134/47/57, B/USSR/60/69, A/Ann Arbor/6/60 and B/Ann Arbor/1/66. With the exception of the A/Len/134/47/57 strain, all are presently used as donor strains in the production of seasonal LAIV vaccines.
There is currently only one licensed LAIV vaccine in the USA: FluMist, indicated for active immunization of healthy children and adults, aged 5-49 years, against influenza types A and B. The vaccine is now under review for use in children under five. (Follow-up note: based on placebo and inactivated influenza vaccine controlled trials the indication of FluMist recently was extended to the 2 to 5 years old group by the US FDA.) The original FDA approval in 2003 was given to a frozen product. Based on immunological equivalence studies, a refrigerated version was licensed in early 2007. The manufacturer is now also working on the adaptation of its LAIV (A/Ann Arbor6/60 and B/Ann Arbor/1/66) for cell culture based production. The egg-based Russian LAIV is coming back to the market in the Russian Federation. One European manufacturer is developing a new LAIV through adaptation of the Russian backbone strains (A/Len/134/17/57 and B/USSR/6/60) to a cell culture substrate.
Markers of attenuation are well established for all LAIV reference strains presently used as donor strains for LAIV manufacture.
Early animal experimental data suggest that a new class of ‘replication-deficient vaccine’ could be developed in the more distant future, with the plausibility of combining the contrasting theoretical advantages of both LAIV and the inactivated vaccines.
A review of the historical, recent and comparative clinical data at the meeting indicated that LAIVs are safe and effective in the prevention of seasonal influenza, with potential for pandemic use. A presentation of the 50 years experience with the Russian live attenuated vaccine demonstrated a robust data collection with an excellent safety record: no evidence of either genetic reversion or new mutant formation, nor increased allergic reactions either in children or adults. The mean efficacy, based on clinical endpoints, across 126 trials and more than 500,000 adults was reported at 45%, maintained at 33% even when epidemics were caused by antigenic variants not presented in LAIV. Community benefit with LAIV vaccination, particularly with school-based immunization, was also demonstrated.
FluMist clinical efficacy was reported in numerous USA based studies. Original frozen FluMist pre-licensure study data showed laboratory confirmed efficacy levels of 87-93% for H3N2 and type B in young children. H1N1 efficacy was demonstrated through challenge studies with 83% and 85% recorded efficacy against H1N1 challenge in children and adults, respectively. The original adult pivotal trial demonstrated an effectiveness of 24% against a clinical endpoint: febrile upper respiratory illness episodes.
A comprehensive overlook of recent studies in Europe and Asia with FluMist in young infants and children has confirmed high overall efficacy against culture confirmed influenza illness, including comparison with inactivated vaccine. Other comparator studies with trivalent inactivated vaccines were also favourable in both children and adults. Where differences were detected, LAIV appeared more protective both in earlier Russian LAIV studies and more recently with FluMist as well. One historical study in Russia found evidence of indirect protection with LAIV and not with inactivated vaccine in children and teachers.
Greater understanding and more research is required in the context of immunization in asthmatics and in the immunologically compromised. Certain response discrepancies regarding immune response and protection against influenza B compared to trivalent inactivated vaccines requires further elucidation, together with the observed increased hospitalization and wheezing exacerbations in very young children in FluMist trials. Various data presented on shedding and control of transmission showed that the levels of virus shedding were unlikely to cause either secondary infection or reassortment with wild type virus, even in trials with children under 5 years of age in daycare settings where ample opportunity exists for transmission.
LAIVs also appear to offer significant potential for indirect protection, or ‘herd immunity’, potentially resulting in wider community protection through vaccination of school children. Multiple studies across Russia and the USA showed reductions in seasonal influenza related morbidity and mortality, illness and absenteeism among families and teachers of LAIV vaccinated children, as well as the adult population in general. (Historical data with inactivated vaccines from Japan and the USA also support the consideration of universal influenza vaccination of children.) Day-care and school-children are primary amplifiers of influenza in the community. School-based influenza vaccination with LAIV was found efficient to ameliorate the effect of influenza epidemics in adults. This approach could also serve as a model for pandemic influenza responsiveness.
There is increasing evidence for LAIV that it is able to protect in the face of antigenic drift. Immediate, pre-antibody-development protection was also observed in Russian trials. These phenomena are not fully elucidated and will remain the focus of future research. Contrary to inactivated vaccines, anti-hemagglutinin antibody response after LAIV administration is not considered as laboratory marker of effectiveness. The lack of such an efficacy marker for LAIV should be addressed: establishment of correlates of protection for LAIV is desirable for both seasonal and pandemic aspects and should be a research priority.
Another significant advantage is the nasal delivery of LAIVs, meaning less healthcare worker burden without syringe and needle requirements. Other implementation issues around LAIVs, notably the cold chain and multidose potential, need to be optimized for pandemic use and technology transfer. Work is under way to improve stability, as well as multidose delivery. Other production issues include master and working seed establishment through reassortment and/or reverse genetics. LAIV seed viruses are currently produced by individual manufacturers and not in WHO collaborating centers.
Specific Pathogen Free (SPF) eggs are used by one manufacturer to produce LAIV but this is not a regulatory requirement. Promising results were presented from pilot scale cell culture production, potentially providing excellent yields and independence from external egg supplies.
Overall, the wide-ranging exploration of the data and related issues produced no scientific or logistical reason to suggest LAIVs are not an equivalently safe and effective form of protection against influenza as inactivated vaccines, albeit, contrary to the earlier established Russian vaccine, not enough data are available yet for FluMist to secure regulatory approval for the elderly and the adult group above 49 years of age.
Partly due to containment requirements for live H5N1 viruses, clinical studies with H5 pandemic prototype vaccines are limited whereas considerably more progress has now been made in this area with inactivated vaccines:
Mainly due to this scarcity of clinical trial data with pandemic prototype LAIV vaccines, the innate theoretical advantages of immunization with live vaccines under pandemic conditions, such as a one dose schedule, broader cross protection etc. are not yet substantiated. More extensive clinical research is needed with pandemic prototype LAIV vaccines, i.e. H5N1. Clinical trials with the Russian vaccine have had encouraging results using another than highly pathogenic H5 strain. Further work is needed with the US vaccine to develop a reverse genetics based rH5N1 vaccine which infects more reliably than the prototype product.
Present considerations, due to the low but theoretically possible reassortment with a seasonal virus, do not suggest mass vaccination with a live rH5N1 vaccine under pre-pandemic conditions. The potential advantages of an LAIV strategy could come into effect after the pandemic begins.