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Inactivated H5N1 vaccine unmasked immunity in prior recipients of LAIV
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Prior recipients of a live-attenuated avian influenza H5N1 pandemic vaccine were found to have long-lasting immunity that was unmasked after receiving an inactivated H5N1 influenza vaccine, researchers from the NIH and Johns Hopkins University have found.
“The high titer, rapid antibody response following a single dose of unadjuvanted H5N1 [inactivated H5NI influenza vaccine] in a majority of subjects who had received an H5N1 [pandemic live-attenuated influenza vaccine] almost 5 years earlier is clear evidence that H5N1 [pandemic] LAIV priming induced long-lasting B-cell memory,” the researchers wrote in The Journal of Infectious Diseases.
Several groups of participants were included in this open-label, phase 1 study. Group 1 included 11 participants who had previously received two doses of H5N1 VN 04 pandemic LAIV (pLAIV), and group 2 included those who had previously received two doses of H5N1 HK 03 pLAIV. Group 3 included participants who had received two doses of an H7N3 pLAIV. A random convenience sample of 40 individuals who had not received any pLAIV vaccine also was included: Group 4 included 20 participants who received one dose of the H5N1 inactivated H5NI influenza vaccine (ISIV), and group 5 included 20 participants who received two doses.
The H5N1 ISIV was well tolerated, and there were no significant adverse events reported. On day 56, responders in group 1 had an increased frequency of hemagglutination inhibition (HAI) assay response and a higher geometric mean titers (GMT): 82% had a GMT of 112 vs. 40% with a GMT of 120 in group 2, and 50% with a GMT of 76 in group 5.
The researchers also found that in all but on pLAIV-primed patient, serum samples neutralized two or more clades of H5N1 viruses vs. group 5, where serum from only one patient neutralized more than one clade.
“The high titer and high quality, broadly cross-reactive antibody response seen in our study, in which pLAIV priming was unmasked by an ISIV boost, should raise interest in unconventional vaccination schedules that combine different types of vaccines.”
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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William Schaffner, MD
We all know that currently available influenza vaccines are less than optimal. Nonetheless, we promote them vigorously because they afford some degree of protection against this potentially deadly infection for many. The advent of avian influenza in 1997 in Hong Kong catalyzed the scientific and public health communities to re-evaluate our current vaccines and to initiate a series of strategies designed to improve protection against influenza. To my mind, there has been more science directed at influenza in the past 15 years than during the 50 years before that. As an interim result, we now have a greater variety of seasonal influenza vaccines available for use each fall and winter: high dose for seniors, intra-dermal for adults, as well as cell-based and recombinant vaccines.
A continuing research issue is how best to prepare for future pandemics which often originate from avian sources. Vaccines remain the most effective response – the trick is how to create effective vaccines so that they can be made and deployed quickly. This provocative report is an intriguing step in that direction.
First, a bit of background. The use of live attenuated vaccines (LAIV) is attractive because they can be manufactured rapidly — they have a high yield of vaccine virus in eggs — and often provide protection against antigenically drifted strains. Thus, such a vaccine was tested against H5N1 avian influenza virus that caused disease in the Hong Kong outbreak. Although the two-dose vaccine schedule was well tolerated and safe, it did not evoke serum antibody responses in the volunteers. Bummer!
Now it gets interesting. The thought was that this LAIV might have resulted in subclinical priming of the immune system that was not detectable by conventional serologic testing. The volunteers now were given inactivated H5N1 vaccine, which resulted in prompt and robust antibody responses. In addition, the quality of the antibody response was broadly reactive against variant clades of H5N1 viruses. This is good news because H5N1 virus can continue to evolve in nature.
The basic immune mechanisms involved in subclinical priming still need to be sorted out, but these results already open out-of-the-box possibilities. For example, if there were a credible threat of a future pandemic, population priming might be started in advance, followed later by booster vaccination should the pandemic actually happen. Even if all could not be reached with a second dose, it is possible that the initial recipients might be somewhat protected against the most severe consequences of influenza. Stay tuned.
In the meantime, I like to evoke that old French philosopher, Voltaire who admonished us that, “waiting for perfection is the great enemy of the current good.” We still can do a lot of good by using our currently available vaccines. The CDC recommendation is that everyone 6 months of age and older receive influenza vaccine each year. So you don’t have to think about it: Just do it.
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