Adjuvant Boosts Supply of Avian Flu Vaccine

Daniel M. Keller, PhD

October 12, 2014

PHILADELPHIA — A vaccine containing small amounts of influenza H7N9 antigen elicited good immune responses when mixed with a common adjuvant, according to the results of a new study.

"The H7 hemagglutinin is a very poor antigen," said Mark Mulligan, MD, director of the Hope Clinic of the Emory Vaccine Center and professor of medicine at Emory University in Atlanta, Georgia. "We know that from earlier H7 containing subtype vaccines that there is very little immune response to the protein alone."

Speaking here at IDWeek 2014, Dr Mulligan reported that two doses of 45 μg of hemagglutinin antigen raised antibody titers only minimally, but when mixed with MF59 adjuvant, doses as low as 3.75 μg were very effective. The technique may be valuable during pandemics, when vaccine antigen is in short supply, and may help raise antibodies to poorly immunogenic antigens.

The study was also published in the October 8 issue of JAMA.

H7N9 influenza infected people who had contact with live poultry in China in March 2013, causing severe pneumonia. Among 452 laboratory-confirmed cases, 67% of patients were hospitalized, and 37% died (166 patients).

The researchers tested an experimental vaccine made from A/Shanghai/2/13 (H7N9) inactivated virus with or without the oil-in-water MF59 adjuvant containing 9.75 mg of squalene. This adjuvant has been used in licensed influenza vaccines in Europe for several years and has a good safety profile.

Using a randomized design, various doses of hemagglutinin antigen (3.75, 7.5, or 15 μg) were mixed with adjuvant in the field and administered to 700 healthy adult volunteers through injections into the deltoid muscle. Some groups received antigen (15 or 45 μg) without adjuvant. Vaccines were administered on day 0, and a boost was administered on day 21.

Two injections of 15 or 45 μg of antigen alone produced only minimal increases in geometric mean hemagglutinin or neutralizing antibody titers on days 29 and 42. The seroconversion rates were less than 10%. Similarly, a single injection of any dose of antigen with adjuvant did not produce substantial rises in titers.

But for vaccines with adjuvant given as two doses, both antibody titer rises and proportion of responders were very good, even at the lowest dose of antigen.

Higher doses of antigen did not increase the response. Giving adjuvant in only the first 15-μg dose was as good as using adjuvant in both doses. However, responses were not as good if only the second dose contained adjuvant.

Antibody responses were attenuated if participants had received seasonal influenza vaccine in the current or prior season, and they were also attenuated with increasing age of the participants.

Table. Antibody Responses to Antigen (3.75 μg) With MF59

Antigen Seroconversion Rate* % (95% Confidence Interval)
Geometric Mean Titer (95% Confidence Interval)
Hemagglutination inhibition 59 (50 - 70) 35 (26 - 47)
Neutralizing antibody 84 (76 - 91) 85 (69 - 104)

*4-fold titer rise to >40


The safety and tolerability of the vaccines were good, although there was more local injection reaction when MF59 was present (P < .001), with 65% of participants reporting mild pain and/or tenderness. There were no serious adverse effects related to the vaccines.

Dr Mulligan said the results show that even the lowest dose of antigen was effective when administered with adjuvant, demonstrating the dose-sparing potential for this approach. Adjuvant may also be spared by using it only in the first dose. "This is one of those situations where you hope you never have to use it, but you need to have it on the shelf," he said.

Limitations of the study were the lack of data on antibody longevity past 42 days, and the lack of clinical outcomes in terms of protection from influenza.

In an accompanying editorial in JAMA, John Treanor, MD, of the infectious diseases unit at the University of Rochester, in New York, notes that migratory waterfowl represent "a vast reservoir of influenza A viruses" that are an "ongoing threat" that can emerge and cause widespread human disease. Viruses of the H5 and H7 subtypes have demonstrated an ability to cause severe disease.

Dealing With Pandemics

Vaccines will be a critical component of dealing with epidemics or pandemics caused by flu strains, but low antigenicity and the need for multiple doses are hurdles to controlling outbreaks. Dr Treanor wrote that the study provides "important information that expands the available options for confronting pandemic influenza," with the caveat that 2 doses would still be needed, which would present "enormous" logistical difficulties for an emergency vaccination program in the face of an emerging pandemic.

He suggests, with the support of study data, that people could be immunologically primed with a prepandemic single dose of a vaccine containing potential pandemic threat subtypes, such as H5 or H7. They could then receive the pandemic strain at the time of the threat, with immunologic memory providing a rapid rise in antibodies even years later, even if the subsequent vaccine is an antigenic variant from the one used for priming.

Andrew Pavia, MD, chief of pediatric infectious disease and a professor at the University of Utah, in Salt Lake City, commented to Medscape Medical News that it was good to hear that some of the strategies that the US Department of Health and Human Services and its Biomedical Advanced Research and Development Authority have developed to respond to pandemics look like they may work.

"They developed a strategy of stockpiling adjuvant separately so that you could make a vaccine on the fly when a new virus emerged. And with H7N9, they sort of did a proof of concept," he said.

Adding adjuvant turned H7, a minimally immunogenic hemagglutinin, into one that substantially raised antibody. Antihemagglutinin antibody is thought of as the primary protective antibody from flu vaccination.

Dr Pavia said a typical flu vaccine uses 30 μg of the antigen, so at the lowest dose of 3.75 μg that the researchers tested with adjuvant, it would be possible to immunize 8 times as many people with a given amount of vaccine "in a pandemic situation early on if production is slow." He cautioned that adjuvant was mixed into the vaccine at the point of care, so it may be something of a problem to ramp up the procedure for mass immunization.

Dr Mulligan reported serving on a data and safety monitoring committee for VaxInnate Inc and receiving a fee for this service. Dr Treanor reported receiving personal fees for serving on scientific advisory boards for Novartis and Merck and receiving grant support from Novartis, sanofi, CSL, Pfizer, and Takeda. Dr Pavia reported no relevant financial relationships. The vaccine and adjuvant were provided by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority and were manufactured by Sanofi Pasteur (H7N9 vaccine) and Novartis Vaccines (M59 adjuvant).

IDWeek 2014. Abstract LB-2. Presented October 11, 2014.

JAMA. 2014;312:1409-1419. Abstract



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