# 5303
Photo Credit PHIL
After the abrupt reappearance of bird flu in 2003, the United States, along with a number of other countries around the world decided to create a vaccine against the-then-dominant clade 1 `Vietnam’ strain of the H5N1 virus.
The United States produced and stockpiled roughly 20 million doses of vaccine.
The feared pandemic did not break out, but the virus continued to spread across Asia and Europe in wild birds and domesticated poultry, and as it did, it drifted and mutated into several new clades.
As Vietnam got better control of their bird flu problem, detections of clade 1 viruses declined, while in 2006 a new and dangerous strain – clade 2.1 emerged in Indonesia.
Elsewhere in Asia, and Europe, clade 2.2 (`Qinghai’) viruses spread widely and caused outbreaks in dozens of countries, including human infections in Egypt, Azerbaijan, Iraq, China, and Turkey.
And since the middle of the last decade sub-clades 2.3.2 (`Fujian’) and 2.3.4 have emerged and continue to circulate across much of Asia.
We now have more than a half dozen active clades of the virus circulating, and further changes to the virus are anticipated over time.
Making the H5N1 bird flu virus a moving target, and very difficult to create a vaccine against in advance.
With our current technology, it takes roughly 6 months from the detection of an emerging pandemic strain, to having any quantity of vaccine available.
And current studies indicate that it will likely take two vaccinations – several weeks apart – to convey immunity against a novel bird flu virus.
An unforgiving timeline that would be trampled by a fast moving pandemic.
To get around these difficulties, the suggestion has been made that we should consider `priming’ essential workers with an H5N1 vaccination now (or at the start of an outbreak) – in hopes that even a slightly `mismatched’ vaccine would provide some protection until a second `strain specific’ vaccine could be distributed.
Furthermore, it was hoped that those who received an H5N1 shot now might only require a single booster shot during a pandemic.
In May of 2010, Dr. Klaus Stohr, former head of the World Health Organization's global influenza program, wrote in an opinion piece for Nature that the world should consider pre-vaccinating their populations against strains likely to emerge in the future (see The Prime Of Our Lives).
And in 2008, Japan – faced with expiring stockpiles of H5N1 vaccines - began a pilot program to pre-vaccinate essential workers in a `use-it or lose-it’ strategy (see Japan Begins Pre-Pandemic Inoculation Of Health Care Workers.)
Other countries, including the UK, have considered similar strategies (see UK: Considering A `Prime Directive').
The idea of pre-vaccination isn’t farfetched.
In the summer of 2008 we saw a study, published in the August edition of The Journal of Infectious Diseases, which showed that people who received an experimental H5N1 vaccine in Hong Kong 8 years before developed a strong immune response after receiving a single booster shot of a clade 1 H5N1 vaccine.
All of which serves as prelude to a new study, which appears in the March edition of The Journal of Infectious Diseases:
Safety and Immunogenicity of Influenza A H5 Subunit Vaccines: Effect of Vaccine Schedule and Antigenic Variant
Robert B. Belshe, Sharon E. Frey, Irene Graham, Mark J. Mulligan, Srilatha Edupuganti, Lisa A. Jackson, Anna Wald, Gregory Poland, Robert Jacobson, Harry L. Keyserling, Paul Spearman, Heather Hill, Mark Wolff
Abstract
Background. The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus).
Methods. The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 μg of antigen was evaluated in healthy adults 18–49 years of age.
Results. Two doses of vaccine were required to induce antibody titers ≥1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month.
Conclusions. An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting.
A somewhat less daunting press release (see Don't Pitch Stockpiled Avian Flu Vaccine) is available from the Saint Louis University Medical Center.
This study (details are available here) made a number of discoveries, which tend to support the notion of pre-pandemic vaccination.
Researchers confirmed that – as expected - a single non-adjuvanted (90 μg antigen) vaccination did not produce an adequate antibody response. Two shots are required.
They also discovered that two doses of clade 1 vaccine did not produce cross-reactive antibodies to the clade 2 virus, and vice-versa.
But, administering one dose of a clade 1 vaccine, followed 7 to 180 days later by 1 dose of the clade 2 vaccine, produced cross reactive antibodies against both clades.
Subjects who received the two shots 14 or 28 days apart developed a better antibody response than those who received the shots 7 days apart, or on the same day.
Somewhat unexpectedly, subjects who received the two shots 6 months apart developed an even stronger antibody response.
Not really an option during a pandemic, but an added bonus if you are priming a population in advance.
- According to this study, adverse reactions were largely local (mostly injection site tenderness, swelling or redness) and generally occurred on the day of vaccination.
- Less common systemic reactions (primarily malaise, myalgia, & headache) were mostly mild or moderate, and generally subsided over 24-48 hours.
While the global stockpile of existing H5N1 vaccine is relatively small, it would allow us to prime millions of essential workers in advance of - or at the start of - an H5N1 pandemic.
The authors wrap up by saying that despite changes in the H5N1 virus over time, their study confirms the usefulness of pre-vaccination with an antigenically out-of-date H5N1 vaccine.
While we hope we’ll never need it, that is definitely good to know.
