Remarkably, we found that H1N1 viruses are now currently evolving within the human population to abrogate the binding of these antibodies. So, this antibody response was primed in the 1990s by H3, boosted recently with H1, and now H1N1 viruses are evolving to escape the response. Remarkable. 5/

We also found these H1/H3 cross-reactive antibodies in polyclonal sera, but only in samples from individuals born in the 1990s. Ferrets sequentially exposed to an H3N2 virus from the 1990s and a contemporary seasonal influenza vaccine produced the same type of H1/H3 cross-reactive antibodies. 4/

Even more surprising, we found that these cross-subtype antibodies targeted an HA head epitope that was partially conserved between H3N2 viruses from the 1990s and contemporary H1N1 viruses. 3/

We found that a large proportion of monoclonal antibodies isolated from individuals immunized with the 2021-22 seasonal influenza vaccine bound to an epitope on the HA head of both the H1N1 vaccine strain and H3N2 strains from the mid-1990s. 2/

While young children rarely possessed cross-reactive NA antibodies, we found that childhood infections with contemporary H1N1, but not H3N2, viruses can elicit them. 3/

We measured anti-NA antibodies in sera from 155 individuals born between 1927 and 2016 and found that those predicted to be 'imprinted' (i.e., initially infected) in childhood with H1N1 had higher levels of cross-reactive H5N1 NA antibodies compared to those imprinted with H2N2 or H3N2. 2/

Anyone that has been around a lab knows that the trainees really drive the research, while most professors just sort of guide the ship. Most innovation comes from our trainees.

Old professors like me will be able to survive these cuts, but our young scientists and our future will be destroyed.

It is striking how H1N1 and H3N2 have been co-circulating this season with an almost 50/50 split. Usually we see one subtype dominate. The most recent CDC report shows flu activity increasing in the US, still mostly H1N1 and H3N2 with little flu B.

www.cdc.gov/fluview/surv...

I met with the PA Lt. Governor yesterday to discuss our avian flu research at Penn. I found that @lgaustindavis.bsky.social and his staff were super sharp and genuinely interested in learning. We may be entering a period where we heavily rely on states for pandemic preparedness and communication.

Residue 226 of the British Columbia human HA sequence is ambiguous. This can happen with poor sequencing, but in this case I think it is likely because of mixed viral sequence, given the residue # and apparent unambiguous sequence of neighboring residues. 4/

For example, take a look at this paper that we recently published together with @jbloomlab.bsky.social . Jesse's lab led the study and found that single mutations at residue 226 dramatically changed H5 receptor binding preference from a2-3 (bird receptor) to a2-6 (human receptor) binding. 2/

Take home message: an H5N1 pandemic might affect children more than older adults who were primed decades ago in their childhood with H1N1 and H2N2 viruses. 11/12

Most of the vaccine elicited antibodies did not neutralize H5, but were able to mediate ADCC--again, with the biggest benefit to children since they started out with lower antibody titers prior to vaccination. 10/12

Consistent with a recent study by Khurana and colleagues, we found that antibodies elicited by clade 1 H5 vaccines bind to the newer clade 2.3.4.4b H5s. 9/12

Older individuals possessed higher levels of clade 1 H5-reactive antibodies relative to children before vaccination and these antibodies were boosted in participants in all age groups after vaccination with the greatest benefit in children. 8/12

By comparing serum samples collected over a 12 year span, we were able to show that H5 antibody titers correlated better with birth year (and H1N1/H2N2 childhood exposure) rather than age. So, birth year is key here, not just growing older. 6/12

In our study, we measured antibodies against H5N1 viruses in people with different birth years and found that older people who were likely exposed to H1N1 and H2N2 in childhood possessed higher levels of H5 reactive antibodies. 5/12

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