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Sunday, January 01, 2023

A multivalent mRNA flu vaccine

Scientists have recently developed an mRNA-lipid nanoparticle flu vaccine that protects against all known flu variants.

There are four types of influenza viruses but only the A and B viruses cause significant problems [Types of Influenza Viruses]. Influenza A viruses are the ones can have caused pandemics in the past and the current flu vaccinations are unlikely to offer a lot of protection since they are only directed toward the specific subtypes that are predicted to cause problems in the next flu season. The next global flu pandemic will probably come from a new influenza A virus that nobody predicted.

Existing vaccines contain antibodies against the hemagglutinin (HA) surface protein shown in blue in the figure and the neuraminidase (N) protein (red). There are about 18 different HA subtypes (H1...H18) and 11 N subtypes (N1...N11). The most common variants in circulation are the H1N1 and H3N2 combinations.

In theory, it should be possible to create mRNA vaccines against all known variants and administer a mixture of the separate vaccines in order to provide protection against all strains, including those pandemic strains that might arise in the future. An American group has created just such a multivariant mRNA vaccine against 18 different influenza A variants and 2 influenza B variants and tested it in mice and ferrets. The results show that antibodies against all 20 variants were produced and the vaccinated animals survived subsequent flu infections from a influenza strain that was different from any of the ones used in preparing the vaccine.

The next step is to figure out what kind of immunity is being induced by the vaccine. Some of it is due to production of antibodies that block infection (neutralizing antibodies) but it's unclear whether cellular immunity is also a factor. This is important because cellular immunity is what protects against severe disease in the long term - as in the SARS-CoV-2 mRNA vaccines.

It will be several years before these multivariant vaccines are available for humans unless there's a flu pandemic that short-circuits the development and testing phases.

Arevalo, C. P., Bolton, M. J., Le Sage, V., Ye, N., Furey, C., Muramatsu, H., . . . Parkhouse, K. (2022) A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science, 378:899-904. doi:[doi: 10.1126/science.abm0271]

ABSTRACT:Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)–lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactive and subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.


Georgi Marinov said...

>This is important because cellular immunity is what protects against severe disease in the long term - as in the SARS-CoV-2 mRNA vaccines.

That isn't correct.

First, people tried making T-cell vaccines, and the result was zero protection. You didn't see it because it was negative results, and those either don't get published or get ignored (I recall seeing both things happen).

Second. SARS viruses also turn out to have powerful mechanisms for silencing or distorting the T-cell response.

Third, empirically, protection from severe disease decreases with time. It wouldn't be doing that if memory B-cells and T-cells were sufficient.

The only identified correlate of protection is high antibody titers, but those drop fast, and the damn thing is evolving so fast antigenically (because we are giving it the opportunity to replicate at 5-6 orders of magnitude higher rates than it did prior to 2019, and under strong selective pressure too) that loss of actual protection happens even faster than that.

Read this paper:

The antigenic distance between XBB.1/XBB.1.5 and 2019 Wuhan SARS1 is now as large as the distance between SARS2 and SARS1.

And we know that SARS2 vaccines did not protect at all from SARS1 in mouse models. Not even from severe disease. What is saving us from a complete restart of the pandemic is that pretty much everyone got infected with previous Omicron versions very recently, but the winter is far from over yet.

The truly alarming thing is that this happened in less than 3 years.

While the SARS1 and SARS2 divergence dates to decades ago...

Lamarck said...

Hi Georgi Marinov!

“The antigenic distance between XBB.1/XBB.1.5 and 2019 Wuhan SARS1 is now as large as the distance between SARS2 and SARS1.”

And why is that? ;-)