7 reasons why think immunity to COVID from vaccination or infection will be long-lived (and why I continue to marvel that CEOs of companies who stand to make profit from boosters get to message that boosters needed; instead, please donate vax to India).
1. Memory B cells: Image
We discussed this at more length before; remember this amazing memory B cell paper that showed us that 32 people ages 91-101 who survived 1918 flu pandemic STILL had memory B cells that could produce neutralizing antibodies to that strain 9 decades later
Memory B cells last long time & hang out in germinal centers (like lymph node) until they are needed again and then come out to produce neutralizing antibodies against the pathogen. Do we know COVID-19 vaccines produce memory B cells? Yes from this paper
where biopsies of lymph nodes showed memory B cells strongly forming after vaccination. Remember, antibodies produced not just against spike protein (you see a lot of reports on this Ab) but against nucleocapsid proteins (buried deeper in virus basically)
2. T cell immunity generated by these vaccines; we know that for a fact because the phase I/II trials MEASURED T cell immunity generated these vaccines (see column 4 below). Moreover, we know strong T cell immunity generated by natural infection by multiple papers Image
These papers are below, in the following tweet thread () and I will spend minute giving you details of my favorite two papers since they give the longest follow-up duration after natural infection showing that T cell responses have long-half lives Image
This paper by Dan et al. in Science looked at antibodies (from B cells), memory B cells, and memory T cells (both CD4+ and CD8+ cells) from 188 (80 male; 108 female) patients recovered from COVID (93% mild; 7% hospitalized) over 8 months. science.sciencemag.org/content/371/65…
Happily, memory B cells (relevant to reason #1) seen in almost all & half-life of T cells were LONG (~125-225 days for CD8+ and ~94-153 days for CD4+), comparable to the 123 days half-life observed for memory CD8+ cells after yellow fever vax (typically given once in a LIFETIME)
3. Memory T cells: Reason #3-related to 2- but MEMORY T cells form (last long time) as evidenced by this paper from @UCSF showing us CD8 T cells continuously differentiate for ~6 months after infection, into cells with features of long-lived memory T cells
4. T cells from vaccination last long time: Reason #4- We know T cells from vaccines last long time; paper on those who got measles vaccine as children with strong T cell immunity 34 years later. Antibodies can be stimulated by memory B cells-reason 1.
5. T cells from natural infection with a related coronavirus that caused severe disease last long time. Reason #5. SARS-CoV is a coronavirus that- like SARS-CoV-2 (which causes COVID-19) -causes severe disease. Reminder of its course below. However, a Nature 2020 shows us Image
5 (continued) that T cell immunity from those who recovered from SARS in 2002-03 still strong 17 years later showing us that T cell immunity to coronaviruses last long time (again, antibodies may fade but can be produced again by memory B cells: reason#1)
6. 6th reason is that T cell immunity works against variants: hope you are convinced of this - thread here but remember that T cell immunity is very robust, in-breadth, forms across multiple parts of virus (including multiple pieces of spike protein)
7. 7th and final reason is that coronaviruses don't actually mutate that quickly -has strong proofreading mechanism where -if the virus mutates -it goes back and corrects it. Mutations can arise with high rates of replication when transmission is high
but the virus should not mutate like this when cases are at low levels after mass vaccination. HIV and influenza mutate much more quickly than coronaviruses. So, hope with these 7 reasons, hope I've managed to convince you to wait on booster discussion & vaccinate world
To date, no evidence that an adaptation of Pfizer/BioNTech’s current COVID-19 vaccine against key identified emerging variants is necessary. If we ramp up production of current vaccine for rest of world, we will all be safer.
Please listen to the @OctavianReport here where I explain these 7 reasons I hope simply why I think immunity will be long-lived to the COVID vaccine or infection (and why we can concentrate on vaccinating the world instead of boosters); will get past this
Another paper to insert here of memory B cells being produced by natural infection & primed even more by 1 dose of mRNA vax after infection. Remember, memory B cells important for long-term protection & responses to subsequent infection
I am happy to see more & more agreeing that booster shots likely won't be needed & looked like this article used the first line from thread! Remember how complex immune response is when deciding immunocompromised in one arm won't get response in other arm
1more paper from today from same group but this time in naturally infected patients. Took 77 participants with mild infection; antibodies may wane over time (4-11 months) but did bone marrow biopsies in 18 & saw development of long-lived B memory cells
1 more thing to understand about memory B cells formed by vax or natural infection. The antibodies they make evolve in response to the "antigen" (piece of virus) they see. If variant seen in future, your memory B cells can make antibodies specific to it.
1more paper from today from same group but this time in naturally infected patients. Took 77 participants with mild infection; antibodies may wane over time (4-11 months) but did bone marrow biopsies in 18 & saw development of long-lived B memory cells
"Circulating resting memory B cells directed against SARS-CoV-2 S detected in convalescent individuals. ..results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans". This review below
The authors conclude even " mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.". So, you say, "wow, this is great memory B cells formed by vax or natural infection. Tell me more about memory B cells"
Then I say please read this paper from Frontier Sciences where you learn that the beauty of memory B cell is that if re-exposure to the virus occurs "the memory recall response will be faster, stronger, and more specific than a naïve response". Then you say "what do you mean by
"more specific and what about these darn variants". Then I will tell you about this amazing paper published by OHSU recently which mildly says "Unease has arisen over the past several months with the emergence of specific CDC-defined variants of concern"
You then say, "Yes, I have unease, the news tells me every day to have unease". So, the authors stimulated memory B cells from those who had recovered from original (ancestral strain) COVID & looked at antibody responses to mutations in variants of concern. Original Abs may not
work as well against variants, but these memory B cells when they see new virus make new antibodies that are ADAPTED to those new mutations. Memory B cells aren't dumb, they will respond to the stimulation (viral mutations) they see at hand. In fact, these memory B cells
will be "stimulated to expand and differentiate into a new population of antibody secreting cell" that will produce antibodies just right for the new variant of virus they see. Author conclusions? "We contend there is reason for optimism regarding the capacity of vaccination,
"prior infection, and/or both, to limit disease severity and transmission of [variants of concern] as they inevitably emerge in the setting of ongoing transmission". Okay, so this thread has told us
1) T cells induced by even mild infection or by the vaccines differentiate into
memory T cells. Great paper by group at @UCSF showing that memory T cell differentiation after even mild infection here
And another paper by that same great group at @UCSF showing those T cells elicited by vaccine as well - maybe good to get 1 dose after natural infection to stimulate more T cells quantity & more honing to nose (although quality good with natural infection)
2) We have already explained in a prior T cell thread how at least 87 (likely more) T cells line up across spike protein to fight virus so even 13-14 mutations of delta variant cannot phase those T cells
3) New studies above show us memory B cells produced
by either vax or natural infection AND those memory B cells - if they see variant- will be stimulated to produce and expand antibodies specific for that variant. So, think we are getting lot of data now that both T cells (memory) and memory B cells kill variants.
So, think it important to study correlates of population immunity besides antibodies that will fade with time (or your blood would be as thick as cement with antibodies from all infections you've seen!) like easy T cell tests (unlikely to get easy memory B cell test). Dr. Fauci
had said case load of 10,000 in US would signal to him control of virus in our country. We stand at 11,606 today. 1.6% test positivity rate with 53.2% of our total population (65.3%) having had 1st dose. See @NYT website for cases/test positivity
And @CDCgov website for tracking vaccination. So, despite 726,942 tests being done a day (!), test positivity rate still low (1.5%), and cases of 11K approaching Dr. Fauci metric of 10K being control (cnn.com/2021/03/04/hea…).
This to me says that immunity is not just result of vax rate, but natural immunity as well in our country which was sadly hit so hard by pandemic. Combination of both leading to population immunity despite masks being lifted in US (some places since March, CA still masking)
So, agree with Sen Marshall call to now track immunity in our population (calling for T cell assays & other ways to look at correlates of protection as good use of funds. Immunity solution to pandemic (masks, distance, ventilation, tests, tracing tools)
I have lots of optimism if you put together all the wonderful immunological research we have that we are approaching true control in US & other places with high vax rates so makes me want to address global vax equity - have article coming out tomorrow in @sfchronicle on this
Final point: I see concern being raised young children aren't protected until vax but actually protected by low community transmission. There is a concept in HIV called "community viral load" @drmoupali and Dr. Grant Colfax (DPH director SF) paper in 2010
As virus in low circulation in community (10 cases in city of SF despite much testing data.sfgov.org/stories/s/San-…) and 11,606 across US with 1.5% test positivity rate, children protected by this low circulation of virus like "community viral load" concept
I wrote piece on this but doesn't include 1) Latest OHSU paper showing memory B cells will produce antibodies against variants if they see them again; 2) Memory B cells produced in both natural infection (bone marrow) & vax. So much new research!

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More from @MonicaGandhi9

30 Jul
See a lot of despair this morning after CDC announcement yesterday re: high viral loads with delta so transmission risk from vax'd & agree that this virus gives us so many twists & turns and so disappointing. But wonder if this helps about the mysteries
Or changing one's expectations with delta away from #covidzero but seeing that we have made much progress in our fight against this terrible virus; defanging the virus with the vaccines so that in areas of high vax, hospitalizations & cases more uncoupled
Please read @ashishkjha analysis of slides which reminds us of high vax effectiveness against disease & please read this- antibodies take bit of time to make from memory B cells but they do kick in, bring down transmission. T cells prevent severe diseases
Read 6 tweets
29 Jul
Good summary from WaPo on day's issues 1) waiting on CDC data on vax'd and viral load (we will likely need culture for deeper dive); 2) masks @CarlosdelRio7 "putting toothpaste back in tube"; 3) plummeting UK cases: delta-driven natural immunity+ vax
In terms of UK cases falling despite easing lockdowns, not surprising. Delta is a hurricane- if finds vaccinated's nose, will boost immune response if asymptomatic; finds unvax'd adults FAST & tragically causes deaths or natural immunity if non-severe
Of note,- I'm sure CDC has data on viral loads with delta & will tell us. Delta has higher viral load, different beast than alpha. But is a PCR-determined viral load in a vax'd person with immunity (Abs/T cells in nose) as infectious as in unvax'd? Do we need culture to tell??
Read 14 tweets
28 Jul
Bit counterintuitive to think that vaccinated people with antibody & T cell islands in their nose to transmit infection at the same rate as those who are unvaccinated. So, would be good to see data & probably need culture data to confirm not dead viral particles from vax success
However, I think it is about inoculum. If you are vax'd & have high rates of community transmission around you, more likely for virus to get in, cause a mild breakthrough as stimulate antibodies (T cells, which fight severe disease already there)
Delta variant has higher viral loads than alpha or ancestral strain so I am sure -with those higher viral loads, vaccinated people can transmit with mild breakthroughs- However, transmitting at equal rates seems counterintuitive.
Read 4 tweets
28 Jul
Spoke to @fayeflam at Bloomberg last week of how vaccine memory should be long. There are many papers on this but I wanted to give you the 4 most interesting ones in this thread in my opinion.
So, we all love this paper showing the vaccines generate memory B cells (even in the lymph nodes with biopsies) although La Jolla and other places had already shown memory B cell formation in blood in other studies
So you have memory B cells and see a variant in the future? Even if your antibodies wane (which they will, not a glitch but natural for the immune system), you have the blueprint to make more from memory B & those antibodies will ADAPT to the variant
Read 6 tweets
27 Jul
Wanted to explain what @CDCgov did today in terms of masking guidelines & why I think made sense. They did not say everyone mask- they said mask according to community transmission rates + vaccination rate in your community. I, @syramadad @ashishkjha wrote
this article in Washington Post a long time ago saying look at community transmission rates + vaccination rates as metrics of when to lift restrictions (we used a hospitalization metric of <5/100K because case rates can become uncoupled from hospitalizations at higher vax rates)
So, what did the CDC do today? They released this MMWR article saying just that- decide on masking on vaccination rates + community transmission rates. Why? Because we aren't where we wanted to be with vax rates in US by this time & we have the delta.
Read 7 tweets
26 Jul
In this critical time of delta circulating, we need clean data on 1) what % admitted to hospital are unvaccinated; 2) if vaccinated, is it breakthrough or asymptomatic with universal screening; 3) if vax'd, need CT of PCR test or some way to know viral load
This article explains concept of viral load and how to determine from PCR cycle threshold (if that is the test hospital is using); rapid antigen is another test using lateral flow assay
If delta higher viral loads explaining transmissibility,
1) Asymptomatic breakthrough, low viral load: You fought the virus, brought it down & vax success, can't spread
2) Symptomatic breakthrough: Need to know if viral load high enough to transmit
3) Severe breakthrough: Boost
Read 4 tweets

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