Two summers ago, just a few months after China’s first H7N9 outbreak began, we saw the NIH Begin Phase II Clinical Trials On H7N9 Vaccine Candidates, with a projected study period of more than a year.
Unlike the fast-tracked 2009 H1N1 pandemic vaccine – which essentially involved a simple strain change (substituting the swine-origin H1N1 virus for the seasonal H1N1 component) – creating, testing and approving a novel avian flu vaccine is a long-haul project.
Complicating matters, H5 and H7 experimental vaccines have proved poorly immunogenic in the past – requiring unusually large amounts of antigen (up to 12x normal), spread across two shots several weeks apart - to induce a good immune response.
A specification that would greatly reduce the number of shots that could be produced and delivered during the first year of a pandemic.
One way around this obstacle is to add an adjuvant - proprietary ingredients that are added to vaccines to increase the recipient’s immune response and that can dramatically lower the amount of antigen needed in a vaccine.
And in 2013, we saw the FDA Approve Adjuvanted H5N1 Vaccine For National Stockpile for precisely these reasons.
So it was not unexpected when last October, we saw an announcement from the NIH: H7N9 Vaccine Candidate Works Much Better With An Adjuvant. According to their study, which investigated an adjuvant called MF59 - which is widely used in Europe but not licensed in the United States - “Without adjuvant, immune responses produced by the investigational vaccine were minimal regardless of vaccine dosage.”
Fast forward to today, and from the Journal JAMA we have the results of a NIAID sponsored Phase II Clinical trial H7N9 Mix and Match With AS03 and MF59 in Healthy Adults that confirms the earlier finding – that without an adjuvant – the H7N9 vaccine’s effectiveness was abysmal.
The bottom line, without an adjuvant, only 2% of vaccine recipients saw an acceptable immune response (HAI Titer > 40). Two 15 µg shots were still required, but those who received ASO3-adjuvanted vaccines were more likely to mount an acceptable immune response (84%) compared to those who received the MF59 adjuvanted formula (57%).
First a brief excerpt from the press release, then a link to the abstract (full study behind a pay wall).
The JAMA Network Journals
In a phase 2 trial that included nearly 1,000 adults, the AS03 and MF59 adjuvants (a component that improves immune response of inactivated influenza vaccines) increased the immune responses to two doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest amount of antibody response, according to a study in the July 21 issue of JAMA.
Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an hemagglutination inhibition antibody (HIA) titer of 40 or higher was 2 percent without adjuvant (n = 94), 84 percent with AS03 adjuvant (n = 96), and 57 percent with MF59 adjuvant (n = 92).
The two schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean (average) titers (GMTs) than the group induced by two AS03-adjuvanted formulations but higher GMTs than two doses of MF59-adjuvanted formulation. Older age and prior administration of seasonal influenza vaccine were independently associated with a decreased antibody response.
"These results imply that, of the options currently available utilizing adjuvants included in the national stockpile, based on the immune response data, AS03 should be considered a first-line adjuvant for strategies incorporating an inactivated H7N9 vaccine in adults," the authors write.
Original Investigation | July 21, 2015
Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized Clinical Trial
Lisa A. Jackson, MD, MPH1; James D. Campbell, MD, MS2; Sharon E. Frey, MD3; Kathryn M. Edwards, MD4; Wendy A. Keitel, MD5; Karen L. Kotloff, MD2; Andrea A. Berry, MD2; Irene Graham, MD3; Robert L Atmar, MD5; C. Buddy Creech, MD, MPH4; Isaac P. Thomsen, MD4; Shital M. Patel, MD5; Andres F. Gutierrez, MD5; Edwin L. Anderson, MD3; Hana M. El Sahly, MD5; Heather Hill, MS6; Diana L. Noah, PhD7; Abbie R. Bellamy, PhD6
Regardless of what influenza virus causes the next pandemic, the reality is that it will take 4 to 6 months to produce and distribute any meaningful quantity of vaccine, and many people could end up waiting much longer before they see one.
Add in the need for two shots, and the logistics of production and delivery become even tougher.
While having a viable vaccine is an important part of the pandemic preparedness toolkit, in the opening months of any global outbreak we will be looking more towards measures like social distancing, school closures, hand hygiene & masks (aka Nonpharmaceutical Interventions NPIs) along with neuraminidase (NA) inhibiting antiviral drugs (NAIs) like oseltamivir (Tamiflu ®) and Zanamivir (Relenza ®) to help mitigate its impact.