“Insanity: doing the same thing over and over again and expecting different results.”

– Albert Einstein.

Due to its high rate of lethality (30-40%) and pandemic potential, H7N9 preparedness has become a priority for public health officials. While mutations that would enable human to human transmission by the avian strain have not yet occurred, CDC placed H7N9 at the top of the risk scale for both emergence and potential for significant pandemic impact, should human-to-human transmission occur. Over the past 6 months, the number of cases has significantly increased – more than 450 human cases have been reported since last fall.  (See data from Ian Mackay here) Add the news that a new strain of H7N9 has emerged in Tennessee to the mix, and you can see why US health officials (read BARDA, CDC) are concerned. However, candidate vaccines have failed to elicit strong immune responses necessary to protect from infection.

The failure of H7N9 vaccines was predicted. In April, 2013, within days of the publication of the H7N9 sequence, researchers at EpiVax reported that H7N9 virus was a “Stealth” virus, because there were too few T helper epitopes in H7 HA to drive effective antibody response. The scientists compared the new virus with H1N1 and H3N1 and made the prediction before any vaccines were available. The original finding was published in August 2013.

As predicted, vaccines against the new strain were poorly effective: In stark contrast with vaccines for seasonal influenza (H1N1), H7N9 vaccines generated very low immune responses without adding strong adjuvants. Seroconversion rates of only 6% and 15.6% were reported in Phase I clinical trials (as compared to 89% for similar unadjuvanted seasonal H1N1 subunit vaccines). The EpiVax prediction was right on target.

H7N9 is truly “Stealth”. One of the ways by which the immune system detects infection is by presenting short peptides derived from the pathogen to T cells, which distinguish between foreign and self antigens. Researchers at EpiVax and the University of Rhode Island also produced evidence that the H7N9 hemagglutinin (HA) surface protein had evolved a set of mutations that make it similar to human proteins, and the presented peptides thus resemble self antigens, activating and expanding regulatory T cells. These new sequences actively suppressed immune response – a new means of pathogen escape called immune camouflage.

The immune-camouflage hypothesis was tested by challenging peripheral blood mononuclear cells from naïve donors with H7N9-derived peptides. Remarkably, the more the peptide resembled a self-antigen, the less it was able to elicit a T-cell response. To prove the point, EpiVax ‘immune engineered’ a better vaccine by changing the sequence of the H7 HA Treg epitopes. In studies carried out at three independent laboratories (publications in preparation), the vaccine was more effective than “wild type” vaccine. This “optimized” H7 HA vaccine was produced by Protein Sciences Corporation and is currently in clinical trials in Australia. (Thanks Nik Petrovsky!)

What’s the message? Well, before WHO, BARDA and NIH make the decision to order up an entirely new vaccine to protect against the new H7N9 viruses, they should consider whether the new strain is still a stealth virus (contains the Treg epitopes discovered in the original strain). And, in the interest of science, EpiVax scientists would be happy to share their ‘immune-engineered’ fix. If not, BARDA and the CDC will certainly make the same mistake they made in 2013.

What was that definition of insanity? Anyone?