In new work, we show a human coronavirus evolves to escape neutralization by antibody immunity (biorxiv.org/content/10.110…). Specifically, we studied the historical evolution of the common-cold CoV-229E to learn how #SARSCoV2 might evolve & if we might need to update vaccines. (1/n)
We first built a phylogenetic tree of CoV-229E evolution from 1984 to the present, and experimentally reconstructed the spike from viruses at 8 year intervals (1984, 1992, etc; see large black strain names in tree below). (2/n)
Next we tested how well human sera collected shortly after 1984 neutralized each viral spike. Below is serum from 26 yr old collected in 1985: it neutralizes 1984 virus well, but 10-fold less activity against 1992 virus & no activity against viruses after 2008. (3/n)
Sometimes, the loss of neutralization of "future" evolved CoV-229E virus is even more dramatic. Below is serum collected in 1990 from a 28 yr old that neutralized 1984 virus very well, but has no activity against any viruses more recent than that! (4/n)
These results show that the coronavirus is evolving antigenically, so immunity elicited against older CoV-229E is eroded by mutations in spike. For instance, this serum collected in 1995 neutralizes viral spikes from before then, but has reduced activity against new spikes. (5/n)
In contrast, "modern" serum collected from adults in 2020 tends to neutralize all historical viruses (see below for example), suggesting antibody immunity itself is durable: the problem is viral evolution that escapes antibodies to older viruses. (6/n)
We did additional experiments suggesting much of the antigenic evolution is in the spike's RBD, which is the most evolutionarily variable part of the CoV-229E spike, especially in receptor binding loops (see below & paper for more details). (7/n)
Why is spike antigenically evolving so fast given that coronaviruses have lower mutation rates than other RNA viruses such as flu? Well, mutation rate is only one part of evolution, which also depends on how selection acts on effects of mutations. (8/n)
What does this mean for #SARSCoV2 immunity? First, need to emphasize that our work was done in CoV-229E, which is a *different* human CoV. Nonetheless, there is lots of evidence antigenic mutations occur in #SARSCoV2 too (citations in Tweet 13 below). (10/n)
But people should not be alarmed. Human immunity is polyclonal, so even in worst case it would take years to get enough viral mutations to fully escape. Furthermore, even residual immunity to antigenically evolved viruses could reduce disease severity (this is unknown). (11/n)
Furthermore, leading vaccines to #SARSCoV2 using cutting-edge approaches (eg, mRNA) that should make it easy to update spike sequence if there is evolution. So for this reason, we need to carefully monitor virus for antigenic evolution. (12/n)
This is important! If we identify possible antigenic mutations ahead of time, then if #SARSCoV2 evolves to escape immunity like CoV-229E, we can see it happening--and if needed vaccines could be periodically updated as is already done for influenza. (14/n)
Another hopeful thing: we found some people had immunity that was resistant to viral evolution. For instance, serum of 35 yr old below neutralized CoV-229E from 2 decades later. If we learn what makes some immunity evolution-resistant, maybe we can better elicit it. (15/n)
Great collabs, including @GreningerLab. Although >2e5 #SARSCoV2 seqs, few CoV-229E seqs in last decade almost all from @GreningerLab@UWVirology. By sequencing "less popular" viruses, they enabled our study (16/n)
I forgot to include image of serum from 35 yr old that had immunity that is more resistant to viral evolution. Here it is, see how this sera collected in 1986 neutralizes viruses from two decades later. Ideally, a vaccine would elicit sera like this!
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Here is analysis of HA mutations in H5 influenza case in Missouri resident without known contact w animals or raw milk.
TLDR: there is one HA mutation that strongly affects antigenicity, and another that merits some further study.
As background, CDC recently released partial sequence of A/Missouri/121/2024, which is virus from person in Missouri who was infected with H5 influenza.
Here I am analyzing HA protein from this release, GISAID accession EPI_ISL_19413343cdc.gov/bird-flu/spotl…
Sequence covers all of HA except signal peptide, and residues 325-351 (sequential numbering) / 312-335 (H3 numbering). The missing residues encompass HA1-HA2 boundary, and any missed mutations there unlikely to affect antigenicity or receptor binding, but could affect stability.
In new study led by @bblarsen1 in collab w @veeslerlab @VUMC_Vaccines we map functional & antigenic landscape of Nipah virus receptor binding protein (RBP)
Results elucidate constraints on RBP function & provide insight re protein’s evolutionary potentialbiorxiv.org/content/10.110…
Nipah is bat virus that sporadically infects humans w high (~70%) fatality rate. Has been limited human transmission
Like other paramyxoviruses, Nipah uses two proteins to enter cells: RBP binds receptor & then triggers fusion (F) protein by process that is not fully understood
RBP forms tetramer in which 4 constituent monomers (which are all identical in sequence) adopt 3 distinct conformations
RBP binds to two receptors, EFNB2 & EFNB3
RBP’s affinity for EFNB2 is very high (~0.1 nM, over an order of magnitude higher than SARSCoV2’s affinity for ACE2)
Over 4 yrs after being first to publicly release SARS-CoV-2 genome, Yong-Zhen Zhang just published large set of viral seqs from first stage of COVID-19 outbreak in China
Zhang recruited nearly all COVID-19 patients hospitalized at Shanghai Public Health Center in first 2/3 (Jan-Sep) of 2020.
The largest source of Shanghai patients in Jan/Feb 2020 was imported cases from Wuhan or elsewhere in Hubei, thereby providing window into Wuhan outbreak.
Overall, Zhang obtained 343 near-full-length SARS-CoV-2 sequences from 226 distinct patients, including 133 sequences from samples collected no later than Feb-15-2020.
A phylogenetic tree showing these sequences is below.
In new study led by Caleb Carr & @khdcrawford, we measure how all mutation to Lassa virus glycoprotein complex (GPC) affect cell entry & antibody escape
Results show how prospective assessment of effects of mutations can inform design of countermeasures biorxiv.org/content/10.110…
As background, Lassa virus causes of thousands of deaths each year, mostly from spillovers from its rodent host, but there is occasional human-to-human transmission.
Lassa is biosafety-level-4 priority pathogen, & efforts are underway to develop vaccines & antibody therapeutics.
We used pseudovirus deep mutational scanning to study effects of nearly all 9,820 amino-acid mutations to Lassa’s GPC at biosafety-level-2 by making genotype-phenotype linked libraries of lentiviral pseudotypes blog.addgene.org/viral-vectors-…
Here is my brief analysis of Dec-28-2019 SARSCoV2 submission to Genbank.
This analysis supports my conclusion to WSJ () that this submission does not tell origin of virus, but does show sequence known to Chinese Academy of Sciences weeks before released wsj.com/politics/natio…
Here is link to my full analysis:
See also images of the same posted below (although it's probably just easier to click on link above and read HTML). github.com/jbloom/SARS2_2…
I also don't think Genbank/NCBI could have reasonably known at time that this sequence was so valuable given that Chinese govt did not announce they had sequence or had submitted it, and Genbank receives vast numbers of submissions.