Commentary
Universal
Vaccine Media Myths
Recombinomics Commentary
12:55
February 23, 2009
Researchers claim that these antibodies protect against easily-transmitted H5N1 even when given to mice three days after they were infected and kept them immune for up to three weeks.
The above headline and comment from media reports on the antibody treatment describe in today's Nature Structural and Molecular Biology, "Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses" paper unrealistically raise expectations and misrepresent the data presented in the paper. These media myths are repeated and create many misconceptions, which can be significant downside in the management of seasonal and pandemic influenza. They create an illusion of a near term universal vaccine that can lead to a single injection that will give long term protection against a wide range of influenza's, including various seasonal flu serotypes and pandemic influenza.
However, the paper does not describe a universal vaccine. It describes a panel of monoclonal antibodies that can provide protection from an influenza challenge in mice treated before or after infection. The data on treatment prior to infection is for one day, while the longest time period reported post infection was 3 days.
The approach has received widespread attention because the antibodies are directed a conserved region of HA, which inhibits viral entry into cells and this inhibition has been demonstrated for a variety of influenza A serotypes. The conserved region has been dubbed an "Achilles' heel" of the virus, but the data in the paper show that high levels of antibody are required, and virus that can partially escape from the treatment already exist in the limited number of isolates tested. Similarly, the table of variations in positions that interact with the antibody is significant, although this region is more conserved than the variable region of the molecule that is more commonly linked to immune escape.
The antibodies described in the paper are not vaccines. A vaccine would be the "Achilles heel" that would be injected into hosts to achieve long term immunity against a variety of challenges. The monoclonal antibodies in the paper were selected from a library of antibodies that were selected from an unvaccinated host. The library was screened for binding to clade 1 H5N1, and positive antibodies were expanded and subsequently tested.
When used at high concentrations, the antibodies could protect from lethal challenge, by the clade 1 H5, or other serotypes, including H1. However, full protection required high levels of antibody (10-15 mg /kg), which would translate to approximately 1 gram of antibody in an adult human. When the antibody levels were lowered to 2.5 mg / kg, challenged mice began to die. Similarly, differences were noted within sub-types, demonstrating that natural escape mutants were already in circulation.
The requirement for high levels of monoclonal antibodies present serious practical considerations. Monoclonal antibodies for the treatment of various chronic conditions already exist and provide insight into the cost an utility of antibody treatment. Humira is approved for the treatment of rheumatoid arthritis. However, it is used at a dose of 40 mg/injection, or 1/25 of the level used in the mice experiments. Of greater concern however is the duration of a therapeutic dose in vivo. Monotherapy treatment with Humira requires weekly injections.
In the Nature paper, prophylactic use of the antibodies involved a protocol calling for antibody injection one day prior to challenge. There was no data showing that the antibody treatment would produce similar results when the challenge was days, weeks, or months after treatment. Similarly, the use of the antibody for the treatment of infection, given 1-3 days post infection, shows that the antibody can prevent the virus from spreading, allowing the immune systems of the challenged mice to effectively overcome the infections. None of these experiments tests the durability of the treatment beyond one day (and not for three weeks, as described in the media quote).
However, the media myths suggest that a single injection can provide long term (lifetime?) protection, which is not supported by the data in the paper, or data for other therapeutic or prophylactic monoclonal antibodies. Similarly, the reduced activity against existing isolates suggests that resistance will develop. As was described in the supplemental material, the antibodies interact with a number of positions on the HA molecule, and the change of a single position can reduce binding (efficacy). Thus, although this region is more conserved than the head of the HA molecule, fit variants of each serotype already exist in nature, and immunological escape from a widely used treatment would not be difficult.
Thus, the current approach of using moncolonal antibodies against conserved regions of influenza is a start, but the described approach is not for a vaccine, and the practical or durable application of this approach has yet to be demonstrated.
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