This is a cautionary tale of how anti-Spike antibody may make COVID disease worse. In this study, the authors show that anti-Spike IgG made SARS-CoV disease worse by switching macrophage from wound-healing to proinflammatory phenotype. A thread (1/n)
When rhesus macaques were immunized with SARS-Spike MVA vaccine, high titers of neutralizing Ab (NAb) generated correlated with severe diffuse alveolar damage NOT protection upon i.n. challenge with SARS-CoV, despite reducing viral load. Loss of disease tolerance by S-IgG. (2/n)
Next, rhesus macaques injected with low or high dose of anti-Spike-IgG (passive transfer) and challenged with SARS developed worse disease. Thus, S-IgG alone can lead to SARS disease exacerbation. (3/n)
Anti-Spike IgG fails to prevent viral entry. Instead, it binds to virus, facilitating uptake by macrophages expressing FcR. This leads to macrophage stimulation and their production of proinflammatory cytokines (IL-6, IL-8, MCP1) and loss of tissue-repair cytokine (TGFb). (4/n)
Finally, sera from early stage SARS-infected patients reveal that elevated anti-Spike IgG was observed in those that ended up dying from infection. (5/n)
If these results also apply to #COVID19, targeting Spike as vaccine antigen may have detrimental effects. Passive transfer of anti-Spike mAb alone also may have detrimental effects. A protective vaccine approach may need to include other viral antigens (nucleocapsid?). (6/n)
Relevant to this thread is that in #COVID19 patients, the level of serum IgG against Spike protein correlates with older age, disease severity and lymphopenia. (7/n)
I hope this thread will spur productive discussion by others. Please feel free to chime in. Thanks @aaronmring for your insights that inspired me to post this thread.
Bottomline: we need to carefully consider vaccine approach to #COVID19.
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Vaccines that reduce infection & disease are needed to combat the pandemic. Here, @tianyangmao@BenIsraelow et al. describe our new mucosal booster strategy, Prime and Spike, to induce such immunity via nasal delivery of unadjuvanted spike vaccine 🧵 (1/)
Current COVID vaccines are given intramuscularly. This induces robust circulating antibodies and systemic T & B cell responses that block viral spread and disease. However, to better block infection, immunity has to be established at mucosal surfaces. (2/) annualreviews.org/doi/10.1146/an…
To elicit mucosal immunity from scratch, live attenuated vaccines are often necessary, due to the need to introduce sufficient antigen and innate immune signals needed for priming via mucosal surfaces. Live vaccines are not safe for immunocompromised. (3/) nature.com/articles/s4157…
So excited to be a part of this important study led by @michelle_monje on how significant longterm neurologic damage can occur after a mild respiratory-only SARS-CoV-2 infection. My own🧵on the findings of this study with relevance to #longCovid (1/)
How can a mild respiratory SARS-CoV-2 infection lead to longterm neurological symptoms? Possibilities include 1) direct infection of 🧠, 2) autoimmunity, and 3) inflammatory impact of infection distal to the 🧠. In this study, we focused on 3) 👇🏽 (2/)
To achieve this goal, @peowenlu & @ericsongg used a mouse model developed by @BenIsraelow & @ericsongg in which we can control where the infection happens. Using AAV-hACE2 intratracheally, we can confine the SARS-CoV-2 infection only to the lungs. (3/)
CoronaVac is an inactivated SARS-CoV-2 vaccine approved for use in 48 countries. In collaboration with the Ministry of Health in Dominican Republic, we tested whether CoronaVac (2x) + Pfizer booster induces neutralizing Abs to Delta and Omicron. (1/)
We analyzed plasma samples from 101 participants in Dominican Republic (DR) who received the BNT162b2 booster >4 weeks after the 2x of CoronaVac. We compared them to samples from people at Yale who received 2x of BNT162b2.
⬆️ ⬆️ Ab induced by heterologous prime & boost.(2/)
Next, @carolilucas & @ValterVSM analyzed NAb against ancestral vs. Delta variant. CoronaVac 2x followed by Pfizer mRNA vax booster robustly elevated NAb against both virus types, level similar to 2x Pfizer vaccine. (3/)
This thread is about our new preprint on transposable element called long interspersed nuclear elements (LINE-1/L1). When expressed excessively in the cerebellum, L1 causes ataxia (impaired coordination).
Human genome is occupied in large part by transposable elements or jumping genes. LINE-1 occupies ~20% of our genome, compared to only 1.1% by exons. Some evolutionarily young LINE-1 are still active and are a rare cause of genetic diseases. (2/)
In addition, L1 may even promote the process of aging & age-related diseases in humans. Until recently, research focused on their activity in the germline. Now, their activity in somatic tissues during a lifespan is being studied. Fascinating review👇🏽(3/) nature.com/articles/s4158…
Our new study by @JieunOh9@ericsongg@MiyuMoriyama et al shows that immune priming via intranasal route provides superior protection against heterologous respiratory virus challenge. The key is in inducing local secretory IgA with broader coverage. (1/)
Mucosal surface epithelium expresses polymeric Ig receptor (pIgR), which transports dimeric IgA + J-chain secreted from plasma cells within the tissue, across to the luminal side. IgA dimer + J-Chain + part of pIgR is released as ‘secretory IgA’. Figure by @BioRender. (2/)
The secretory IgA can bind viruses, bacteria, toxin in the lumen of intestine and neutralize them. Advantages of secretory IgA is the extended longevity as well as having 4 Fab instead of 2 Fab (monomeric IgA) to bind to the antigen. Secretory IgA is well studied in the gut. (3/)
Despite a number of studies, whether HIV infected individuals are at higher risk of COVID-19 diagnosis, hospitalization, and mortality remains unclear due to variable results found in the population studies, cohort studies, and case series. (2/)
People with chronic HIV infection have distinct immune profiles, such as reduced IFN-I, chronic inflammation, CD4 ⬇️, CD8 exhaustion, poor B cell responses, which impair immune defense against SARS-CoV-2. (Beautiful figure 🎨 by @YYexin) (3/)