enterpriseF-love

Um some people asked for a simplified explanation but the comments seem to be removed? Soo before I call it a night and since I took the time to write it.. this study can be summed up with this:

The longitudinal tracking of RBD-specific clones revealed a more complex picture with a progressive remodeling of the MBC repertoire, refining clonal hierarchy against BA.1 epitopes, and resulting in a clear improvement in both overall affinity and neutralization breadth. While overall functional variations were clearly more subtle than what can be detected over time in newly vaccinated individuals, our results suggest new cycles of GC maturation for naive B cells and vaccine-induced MBCs following BA.1 breakthrough infection... Altogether, the remodeling of the MBC repertoire upon BA.1 breakthrough infection is in line with a recent theoretical modeling study pointing towards the GC reaction during a secondary reaction as a key mechanism to reintroduce diversity in the MBC pool.

This means that in people with 3 doses that were infected with BA.1, their immune response evolved to better handle BA.1. Over 6 months, BA.1 infection remodels the memory B cell repertoire (good) which combats negative effects from imprinting. By doing so, this process of affinity maturation created very potent antibodies that are capable of recognizing future variants. This has implications for our vaccines.

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More in depth:

This work contributes to immune imprinting and how it affects the immune response from our BA.1/BA.5 boosters. Immune imprinting or OAS refers to the phenomenon where sequential infections with distinct antigenic strains will preferentially boost antibody responses against epitopes shared with the original strain. This almost dampened immune response is an issue because we care about how our body will react to future variants and updated vaccine boosters. The prevailing logic is that boosting with an adapted vaccine is meant to prep our bodies against future presumed-related variants. So if we boost with BA.5, we should expect higher antibodies specific to BA.5, otherwise why bother updating the vaccine? However, with the new BA.5/BA.1 boosters, we observed only small increases. It was expected and not a failure of the vaccine formulation per say nor the policies governing the decision to deploy them. It's been established now that breakthrough infections + omicron boosters elicit a response that is dominated by boosting pre-existing cross-reactive B cells. This causes the production of antibodies that either dominantly target the old Wuhan strain (WT) or cross-react to Wuhan + omicron strains. We see very very little neutralizing antibodies specific to omicron however these observations are heavily influenced temporally. What was previously described is what's been observed at short timescales (~1 month). After the bivalent rollout, labs around the world rushed to test the immune response. Early data was not set up to detect these complexities (even if they wanted to). Most simply looked at levels of antibodies and how well they did to take out various strains after the booster. They looked at immune responses from 3-5 weeks after boost and at that point the antibodies being made are from memory B cells from the original vaccination. This early response showed that bivalent boosting resulted in mobilization of clones that targeted conserved epitopes on the spike rather than mobilizing naïve B cells specific to mutated new BA.1 residues. That does not mean the bivalent boosters were useless. There have been a plethora of studies displaying added benefits of taking the bivalent booster in the face of the newest variants (BQ.1.1, XBB etc.), particularly in improving protection from severe illness. The fact is that over time, these B cells undergo affinity maturation which results in better affinity and neutralization potency. This means that antibodies at ~6 months specialize in taking out omicron. Not only that, memory B cells mutate and evolve increased breadth which is exactly why we want updated vaccines. Imprinting can be overcome albeit slowly.

Going forward, there are new questions. Does this occur with our recently significantly drifted variants? Would a monovalent targeted vaccine work better than our bivalent ones? We're essentially priming with a half dose atm. Antigenic distance may increase naive B cell stimulation but that is no guarantee larger distances would generate better neutralization after boosting. What about polyvalent vaccines excluding WT? Should we expect a better response if we do a 2nd bivalent boost? What if a new more severe variant pops up and is derived from the ancestral strain? Imprinting then might instead prove useful. How about the contraction phase, do these new antibodies decay slower? Fun stuff to think about.

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For the actual immunology, off the top of my head these are some that I kept track of in the last 6 months that address this imprinting issue. They each tackle different aspects at different timepoints:

1) Cao et al.

2) Park et al.

3) Schiepers et al.

4) Addetia et al.

5) Kaku et al.

6) Alsoussi et al.

7) Bhattacharya and Victora

8) Hoehl and Ciesek

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What we're currently seeing is an unfortunate and expected consequence of widescale population spread which has led to antigenic shifted or drifted strains that display extreme immune evasion. We adapted to this by updating our vaccines (albeit late) which should some provide protection against future variants but we are still at risk for the advent of another "omicron-like" event. Long term mitigations should endeavor to roll out mucosal vaccines to lower transmission itself. Something also needs to be said for the public health aspect as well. Even if we design the perfect vaccine that mitigates imprinting and deploy it in time, we need to significantly increase actual vaccine uptake and address equity.

Before anyone gets too excited about efficacy data, this report mainly reports reactogenicity/immunogenicity. It's nice to finally see this data though, sIgA at 42 days is encouraging with a lot less side effects. T cell responses are comparable between Covaxin/BB154 as well. The issue I have with mucosal vaccines is that we still direly need more data on immune correlates associated with protection from transmission and either asymptomatic or symptomatic infection. There have been some other vaccine candidates chasing sterilizing immunity but it feels like there's no sense of urgency in further developing them (at least in the US). That said, mucosal vaccines to curb transmission should definitely be the future. Rapidly waning yearly boosters to chase variants isn't going to work (as if it ever was).

Although we did not observe any breakthrough COVID-19 cases in either of the groups, illness visits were not scheduled, and routine SARS-CoV-2 nucleic acid testing was not conducted. Therefore, the results reported here do not permit efficacy assessments, which require large-scale studies to evaluate the reduction in the severity of breakthrough infections and transmission.

Watching this for the plot.

Plot = Enterprise F

No but seriously, I'm intrigued. Hope this season spends more time in space + gives a fitting goodbye for the crew.

The chronic infection hypothesis for novel SARS-CoV-2 variant emergence is increasingly gaining credence following the appearance of Omicron. Here we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately two-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution result in the emergence and persistence of at least three genetically distinct genotypes suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.

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Some noteworthy stuff

• Patient in their 60s infected with B.1.517 with a history of diffuse large B-cell lymphoma underwent allogenic haploidentical stem cell transplantation in 2019 but in 2020, the disease relapsed requiring a new chemotherapy regimen. After chimeric antigen receptor T cell therapy in mid 2020, the disease improved up until November 2020 where it began to relapse again and the patient first tested positive for SARS-CoV-2. The patient was started on palliative radiation therapy on day 278 and was admitted 3 times between days 279-452 for malignancy related complications. Patient also received regular IVIG infusions until day 205 and displayed low IgA, T cell, lymphocyte counts throughout the infection.

• Patient was largely asymptomatic for the duration of infection aside from initial presentation with mild upper respiratory symptoms requiring no hospitalization. Patient also received bamlanivimab on day 90 but subsequently refused further therapy/vaccines

• We measured SARS-CoV-2 viral genome copies using RT-PCR and performed whole-genome sequencing on 30 samples. We tested a subset of twelve for infectious virus and found the individual was infectious with high virus copies for almost the entire duration of their infection (Figure 2B). Nasal swab samples collected from day 79 to 471 post-diagnosis had a mean RTPCR cycle threshold (Ct) of 25.50 (range: 15.6 to 34.1), equivalent to 3.10×10⁸ virus genome copies per mL (range: 7.30×104 to 6.04×10^9), though the genome copies numbers tended to decrease over time (Figure 2B, Table S1). Of the 12 swab samples that we tested for the presence of the viable virus, the infectious virus could be detected in vitro from ten sampling points (between days 79 and 401) but not on days 394 and 471, corresponding to samples with higher Ct values (33.6 and 30.9, respectively; Figure 2B, Table S1).

• We found a higher abundance of non-synonymous than synonymous changes in five of the eleven SARS-CoV-2 genes, including the spike. This suggests positive selection during the course of the infection. Interestingly, although we detected the spike:E484K substitution, it did not reach fixation and lasted for approximately three months following bamlanivimab (LY-CoV555) treatment. This suggests that despite E484K being associated with antibody evasion, it is not necessarily a hallmark of chronic infection involving an immunocompromised person, consistent with previous reports. Since we propose that iSNVs that reached near fixation (spike R809P and T936A/N) could be selectively advantageous during chronic infection. However, the trajectories of the majority of the mutations showed random fluctuation over time suggesting weak selection overall and a predominance of neutral evolution. Furthermore, we hypothesize that spike Q493K/R mutation could be important for chronic SARS-CoV-2 infections, even though neither became fixed in our study because they were on different genotypes.

All contestants:

Winners

• Samuel Albert (France S10)

• Luciana Berry (Brazil S2)

• Ali Ghzawi (Middle East + North Africa S3)

• Charbel Hayek (Middle East + North Africa S5)

• Buddha Lo (USA S19)

• Nicole Gomes (Canada S5 All-Stars)

• Dale MacKay (Canada S1)

• Begoña Rodrigo (Spain S1)

• Gabriel Rodriguez (Mexico S2)

• Sylwia Stachyra (Poland S7)

Finalists

• Sara Bradley (USA S16)

• Dawn Burrell (USA S18)

• Amar Santana (USA S13)

• Tom Goetter (Germany S1)

• Victoire Gouloubi (Italy S2)

• May Phattanant Thongthong (Thailand S1)

"He can rewrite existence and shatter timelines. You cannot trust him"

Ooo could Janet be referring to the birth of the TVA?

The special effects look flat out incredible!! Hoping they show how fearsome Kang really is, a threat to the whole multiverse itself. February is waaay too far off