One of the major issues as we move through the pandemic is how we approach vaccination in the elderly, given severe outcomes are still occurring in this group. We have found that SARS-CoV-2 neutralisation following third dose is impaired in the elderly. medrxiv.org/content/10.110… Surprisingly, the impaired neutralisation was despite similar levels of anti spike IgG antibody concentrations in the blood when younger participants <70 were compared to those >70. This means that somehow younger people are making better antibodies and not simply more of them

Moving back to molecular virology, thrilled to be communicating our new paper on a topic close to our hearts: the virus-host interaction and involvement of cell cycle associated proteins. embopress.org/doi/abs/10.152… We found that productive SARS-CoV-2 infection induces cell cycle arrest and depletes cyclin D from infected cells. Surprisingly, cyclin D3 degradation induced by SARS-CoV-2 promoted infection not via cell cycle arrest, but by relieving cyclin interference with virion assembly.

Our paper on NTD's role in TMPRSS2 usage/cell-cell fusion is out! N terminal domain is the interface for MERS CoV and its receptor. SARS-CoV-2 uses the receptor binding domain to bind ACE2 and the role of SARS-CoV-2 NTD is unclear. cell.com/cell-reports/p… We had previously reported that the H69V70 deletion found in Alpha NTD increased spike mediated entry, and that Alpha was highly dependent on this deletion for infectivity and cell-cell fusion efficiency. cell.com/cell-reports/p…

COVID-19 vaccine elicited immune responses in Africa are understudied. We teamed up with The Nigerian Institute for Medical Research (NIMR) to examine AZ vaccine responses in the context of background prior infections and breakthrough infections. citiid.cam.ac.uk/wp-content/upl… We first measured baseline SARS-CoV-2 seroprevalence prior to vaccination using flow cytometry methods for binding antibodies to nucleocapsid (N), coupled with virus neutralisation approaches for protective neutralizing antibody responses to VOC (January 2021)

Our paper on HIV-1 intrahost evolution under antiviral therapy out after >5 years in the making. @steveo_kemp R Goldstein, A Derache, @Tuliodna D Martin @CollinsIwuji ANRS TasP. Major implications for SARS-CoV-2 and resistance to therapeutics : journals.asm.org/doi/full/10.11… Here we wanted to study HIV-1 evolution within individuals who were unable to suppress the virus with antiretroviral therapies. This was mainly due to sub optimal adherence to treatment, as drug levels in blood were measured and often low. Main findings:

Quick explainer on some of the key findings in our recent paper. nature.com/articles/s4158…. We find Omicron spike binds ACE2 better than Delta. Both variants replicate similarly in nasal cell cultures, but in airway cells high in TMPRSS2 there was significant impairment for Omicron Spike cleavage by furin proteases during virus production in cells allows spike to use TMPRSS2, a cell membrane protease. Omicron (grey) is impaired in cell entry relative to Delta (orange) and Wu-1 (black) when TMPRSS2 (T2) overexpressed; ACE2 (A2) levels impact effect size (R)

Preprint on Omicron updated with further findings. Firstly, we see that the spike has altered its preference for the receptors it uses. SARS CoV-2 entry into a cell can occur via two routes: one that only needs ACE2 and another that needs ACE2 and TMPRSS2. biorxiv.org/content/10.110… TMPRSS2 (T2) is higher in the lower airways and so virus goes the second route in those areas. Omicron spike has reduced ability to use the ACE2+T2 route and doesn't respond to higher T2 levels, unlike Delta in the figure. Also, Omicron entry is not blocked by drugs against T2.

Sharing some potentially significant findings relating to Omicron given the current situation. First of all huge thanks to the team working flat out- Bo Meng, @isabella_atmf and to our collaborators both in G2P, J2P along with @SystemsVirology. Findings as follows: 1. Omicron Spike protein mediates deficient cell entry and is inefficiently cleaved compared to Delta spike. We tested viral entry mediated by Wild Type, Delta and Omicron spikes using a pseudotyped virus system, infecting primary 3D lung alveolar organoids.

Sharing our updated pre-print on Delta Variant and emergence, replication and immune evasion properties. We previously reported partial evasion of neutralising antibody responses following vaccination and breakthrough in vaccinated health care workers. biorxiv.org/content/10.110… We now further define Delta immune evasion using a panel of 38 monoclonal antibodies, showing significant loss of potency of NTD and RBD targeting antibodies. Imdevimab, part of the REGN2 dual monoclonal antibody cocktail is compromised by Delta.

Sharing our Delta work with @AnuragAgrawalMD @flaxter @DrSamirBhatt @wendybarclay11 @CambridgeBRC @Gui_Pap , INSACCOG, Leo James lab LMB, proposing Delta’s explosive emergence in India lies in increased transmissibility combined with immune evasion. researchsquare.com/article/rs-637… Is Delta 25% more transmissible😑? 50%😳? 100%😱? Read on for the answer...But first: we argue that transmission is only half the story! Breakthrough infections and our lab studies point towards significant immune evasion, something seen with Beta and Gamma (but not Alpha).

Following the prelim data presented last week, here is our pre-print on B.1.617. Key points: 1. B.1.617 appears to have modestly reduced in vitro susceptibility to neutralising antibodies generated after vaccination. biorxiv.org/content/10.110… 2. We show that vaccinated individuals can be infected with B.1.617, but without severe disease. The data go some way to explaining the dominance of this variant in a partially immune population, but highlight that vaccination is still protective for the majority of people.

Given the dire situation in India and questions regarding the new variant B.1.617, the so called ‘Double Mutant’ we are sharing some prelim analyses on viruses with either or both of the mutations E484Q and L452R in the critical receptor binding domain that our antibodies target One key question is whether these mutations together are able to overcome immunity from vaccines and natural immunity from past infections. We tested serum from 9 young individuals (<50 years old) who had one dose of the Pfizer vaccine 4-12 weeks prior to the blood sample.

Sharing our analysis of neutralising antibody responses following Pfizer vaccine and convalescent plasma against B.1.1.7+/- E484K Spike pseudotyped virus. Big thank you to the team that made this possible @CUH_NHS @CambridgeBRC @OH_wellbeing @RealMcCoyLab nature.com/articles/s4158… Antibody levels were much higher after the second dose as expected. Following the first dose, three times more serum was needed to block B.1.1.7 and following second dose around two fold more. This small change is only likely to be relevant in those with low antibody levels.

Following on from the first dose Pfizer data below where 7/15 participants above the age of 80 did not achieve neutralisation of virus, we report that all 15 have achieved neutralisation 3 weeks after second dose.

https://twitter.com/GuptaR_lab/status/1350131626240598019

It could be that >80 yo are slower in mounting responses but this is unlikely and also leaves people vulnerable despite vaccine. Remember >80 y o are not featuring in trials so they might still get severe disease. Pre print to come but significant delays.

Sharing some real world data on antibody responses to the Pfizer mRNA vaccine. We tested serum from 23 participants (median age 82) vaccinated with the first dose 3 weeks previously. Serum IgG antibodies against Spike were measured with a luminex assay. Virus neutralisation by participant serum was measured with a virus pseudotyping system where virus particles are made that express the SARS-CoV-2 Spike protein. The figure shows that the two were correlated.

B1.1.7 has more than 20 changes in genetic code, of which 8 are in the Spike protein (shown below). Spike is the target of many of our immune and vaccine responses. These changes can alter the shape of the spike, and that is why scientists are worried about viruses like this. The numbers infected with B1.1.7 has been growing faster than other UK variants based on independent data sources. This variant of SARS-CoV-2 is therefore thought to be more transmissible by around 50%. Data suggest it does not lead to more severe illness however.

The first evidence of in vivo SARS-CoV-2 escape from antibodies: emergent Spike deletion H69/V70 and D796H mutation in a convalescent plasma (CP) treated patient. These mutations conferred reduced susceptibility to the CP and sera from multiple donors. medrxiv.org/content/10.110… Clinical case summary. Individual with lymphoma treated with B cell depletion therapy (rituximab).