Hensley Lab Profile picture
Nov 25, 2022 12 tweets 6 min read Read on X
We developed a new multivalent mRNA vaccine against all known influenza virus subtypes. Our study describing the vaccine was just published in @ScienceMagazine. 1/n
science.org/doi/10.1126/sc…
We created an mRNA vaccine expressing HAs from all 20 flu types. First, we vaccinated mice and found that this multivalent vaccine elicits robust antibody responses reactive to every HA. 2/n
Our new vaccine does not simply elicit antibodies that cross-react to every known influenza subtype. Instead, we found that that the vaccine elicits distinct antibody lineages against all 20 different flu HAs. 3/n
The vaccine elicits both neutralizing and non-neutralizing antibodies against diverse influenza subtypes with pandemic potential. 4/n
The vaccine protected mice against viruses that were similar to the vaccine components. But more importantly, the vaccine prevented severe disease and death against viruses that were distinct from the vaccine components. This resembles a pandemic situation. 5/n
And that is our goal: to elicit a baseline level of immunity in the population that would not necessarily prevent infections with new pandemic strains--but rather prevent severe disease and death caused by new pandemic strains. 6/n
Here is an important part: we found that our vaccine elicits strong antibody responses in animals with and without prior flu exposures. We think that this vaccine has the potential to elicit responses in children, as well as the rest of us who have already encountered flu. 7/n
We found very similar results in ferrets. The vaccine elicited antibodies against all 20 HA components and protected animals from an antigenically distinct viral strain. Thanks to @Lakdawala_Lab and @SageVle
for completing ferret experiments. 8/n
We are now testing the vaccine in non-human primates and planning phase 1 human studies. We think this vaccine has the potential to elicit immunity that could be quickly recalled to significantly reduce severe disease and death from our next flu pandemic. 9/n
We've been working on this multivalent mRNA flu vaccine for years--most of this work was completed before the COVID pandemic. I'm grateful to work with the brilliant @WeissmanLab, and I'm so happy to see how mRNA vaccines proved to be so useful during the COVID pandemic. 10/n
Last but not least, I want to acknowledge my lab--especially @pennbgs @IGGPenn graduate student, Claudia Arevalo, who completed most of the experiments for this study. I also acknowledge @NIH, @CEIRRNetwork, and @PennMedicine for their support. 11/n
Thank you @akelvinlab for writing such a nice perspective of our study. 12/n
science.org/doi/10.1126/sc…

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More from @SCOTTeHENSLEY

Nov 3
I’m excited to see our paper posted @medrxivpreprint showing that older folks have higher levels of antibodies that recognize H5N1 viruses compared to younger individuals. Finally some good news for old people. 1/12 medrxiv.org/content/10.110…
You may be asking: how the heck do humans have immunity to H5N1 since these viruses have not circulated widely in humans? As it turns out, there are some rare epitopes that are conserved between H5N1 and certain seasonal influenza viruses that have circulated in the past. 2/12
Influenza A viruses can be broadly split into 2 different phylogenetic groups. Group 1 (H1N1 and H2N2) and group 2 (H3N2) viruses have circulated during distinct times since 1918 and our birth year largely predicts which of these viruses we encountered during our childhood. 3/12 Image
Read 12 tweets
Jan 9
Check out our new manuscript on
@medrxivpreprint. We show that ‘immune imprinting’ with ancestral SARS-CoV-2 mRNA vaccines is beneficial for priming neutralizing antibody responses against emerging SARS-CoV-2 variants. 1/n medrxiv.org/content/10.110…
We first evaluated BA.5 ‘breakthrough infections’. Similar to other studies, we found that these infections elicit strong BA.5 neutralizing responses that are completely cross-reactive to the ancestral SARS-CoV-2 spike (check out absorption data on right). 2/n Image
We next evaluated responses elicited by two BA.5 exposures. Again, similar to one BA.5 exposure, antibodies elicited by two BA.5 exposures were completely cross-reactive to the ancestral SARS-CoV-2 spike. 3/n Image
Read 12 tweets
Sep 29, 2022
@biorxivpreprint just posted our new manuscript showing that IgG3 antibodies are much better than IgG1 antibodies at recognizing flu and SARS-CoV-2 variants. This is a story of basic research having immediate clinical implications. (1/8)

biorxiv.org/content/10.110…
We started by cloning a bunch of flu antibodies that had the same variable domain with different constant domains. Conventional wisdom says that antibody constant domains do not affect antigen recognition. (2/8)
Consistent with conventional wisdom, when we tested binding of these antibodies to influenza HA, we found very little differences in binding (check out all of those 'ns')...but that is not the whole story.... (3/8)
Read 8 tweets
Jul 8, 2022
Our manuscript evaluating mRNA-based H3N2 vaccines in mice was posted on bioRxiv. Most of these studies were completed before the pandemic, and it is nice to finally get this one out. 1/6

biorxiv.org/content/10.110…
Most human influenza vaccine antigens are produced in fertilized chicken eggs. Recent H3N2 egg-based vaccine antigens have limited effectiveness, partially due to egg-adaptive substitutions that alter the antigenicity of the hemagglutinin (HA) protein. 2/6
We now all know about mRNA vaccines since they have been so useful during the COVID pandemic. In the context of influenza vaccines, mRNA-LNP-derived antigens are not subject to adaptive pressures that arise during the production of antigens in chicken eggs. 3/6
Read 6 tweets
Jun 17, 2022
This is a really interesting paper tracking Omicron immune response in health care workers with different SARS2 exposures. This is an amazing cohort and great study but I disagree with some of the conclusions of the paper... 1/7

science.org/doi/10.1126/sc…
The most interesting data in the paper are in Figure 4. This figure includes samples from HCWs infected with Omicron who were (pink) or were not (black) previously infected with the original strain of SARS2. All of these people were vaccinated 3 times with an mRNA vaccine. 2/7 Image
Results from Figure 4: Individuals with prior SARS2 infection who were then infected with Omicron had a boost in N Abs. This is expected since the N protein hasn't changed much. But these individuals did not have a great spike Ab response (for example, RBD below). 3/7 ImageImage
Read 7 tweets
May 31, 2022
Our @CEIRRNetwork funded study reporting an H3N2 antigenic mismatch during the 2021-2022 Northern Hemisphere season was published today @CellReports. This provides an immunological explanation for the ineffectiveness of this year’s flu vaccine.
1 of 4
cell.com/cell-reports/f…
Thank goodness for preprints. We were able to make these data public via @medrxivpreprint in mid-December before H3N2 took off.
2 of 4
H3N2 activity remains unseasonably high in the United States and is taking off in other parts of the world.
3 of 4
Read 4 tweets

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