Covid19, antibody neutralization and the road ahead..

July 15, 2021

I recently wrote a preview for a thought-provoking study by Alexandria Tauzin et al. (Cell Host Microbe, July 2021) regarding the efficacy and associated immune responses following a single dose of BNT162b2 mRNA vaccine (by Pfizer). You can read my preview here, where I discuss some important aspects of immune response discussed in the original paper by Tauzin et al explores few interesting concepts in this study and provides moderate resolution on some burning questions.

There’s been a long-standing debate and confusion about the generation of neutralizing antibodies against SarsCov2 (N and Spike proteins), following single or double doses of mRNA vaccines. Since, I am a scientist and it’s my day job to chop up big questions into smaller pieces.. here are the main questions:

1. When will the neutralizing antibodies be generated following vaccination with 2 doses of mRNA vaccine? How much will the antibody titer be?

2. How can these be detected? What will be the quality of these antibodies?

3. Will absence or weak antibody titer correlate with weaker protection?

4. Will the amount of neutralizing antibodies differ between individuals with a history of natural infection?

5. Will the individuals with prior natural infection require two doses?

6. How will previously infected individuals respond with regards to their humoral and cellular responses?

7. Will the cellular responses fill the slack of weak neutralizing antibodies?

8. Can we predict strong correlations between Th1 and humoral responses?

It has been over 18 months, since we were made aware that a highly transmissible strain of respiratory virus had been going around, and that it has become global. By March 2020, we’d already realized that US was not safe and lock-downs were beginning to shape up. By April, we were starting to lose a disturbing number of individuals daily and it felt like we were in a war. We realized, this was deadlier than anything we had seen and we knew little about how to protect ourselves. By December 2020, however, we had vaccination available and clinical data showed protection. Science has come through and we have found unprecedented results in a historically short timeline. So, what’s next? Here’s what we still do not know:

• How long will the protection last from full vaccination regime?

• How many doses will be required to vaccinate everyone (in the world)? How much time will it take, setting aside the money issue?

Tauzin et al shows that a single dose of mRNA vaccine shows quantifiable protection (humoral and cellular) in those individuals that were previously infected. If that is true, that changes things. We would need less # of vaccine doses world-wide, especially if 12.. 18.. 24 months down the road, we need a booster. So, this is pretty significant. As an immunologist with deep interest in host-pathogen interactions, it seems like there are way too many moving parts to parse through. Focusing from the viewpoint of pathology, it is elusive (still) what contributes towards long-covid. We haven’t a concrete clue in how to prescribe and diagnose for long covid in real time, let alone… retrospectively. I want to do a follow up and connect these studies to more basic immunology as we do in the Khanna lab, to keep this stream of consciousness flowing.

Let’s keep this conversation going, so please comment/discuss your ideas.

Inspired and ready

This year, I co-organized my very first symposium, Inspire Science Symposium 2020.
So, I wanted to write about it and jot down things that I learned, worked and could use work in future. It’ll take me a few posts to really log the nitty-gritties, so bear w/ me.

Part-1.
What is Inspire Science Symposium?
The Inspire series started years ago with a bunch of hopeful trainees that got together and created a space to celebrate (their) science, and the baggage it came with. In part, to find individual journeys after graduate/postdoc training as well as to find what tools lay in individual arsenals in order to find those journeys. What’s really unique about this symposium, is that it tackles the need for skills required beyond just science. Skills such as communicating the science, passing it on and most importantly, making it applicable to the society. And so, since its inception over a decade ago at UCSF/Berkeley, The InspireSci Symposium Series aims to nurture scientists and expand their skills by offering a variety of topics such as science outreach, communication, networking, etc.

Sponsored by the Institute for Systems Genetics at NYU School of Medicine, 2019 edition of InspireSci broadly dealt with the topic of science outreach. But, this year, things were different. Unlike last year, we couldn’t have more than a few people in a seminar room… let alone a crowd of 100+. So, the symposium had to be virtual, and it had to set itself apart from any other online event. So, it required a brilliant idea, lot of organization, willing invited speakers and the right time.

First things first: how’d I get roped into this?
Two words, Ada Weinstock.

Ada is a K99 postdoc fellow at NYUSOM. She’s a friend, (an unofficial) mentor and someone I deeply admire for her science, her tenacity …among many other things. My first interaction w/ Ada was back in 2018, in a group meeting. I was so taken by her brain, that I actually went up to her after the meeting and asked, “Who are you?” She shot back, a little louder, the same and we’ve become friends since.

Ada sent me an email in early July about joining the InspireSci team w/ very little insight other than, “..I think you’ll be perfect at this!” July was a tricky time to take on more, considering we had just been back in labs for a few weeks and things were starting to look up for experiments. Albeit hesitantly, I said yes because I trust Ada. With the general theme of Staying inspired in uninspiring times, the InspireSci team assembled and began coordinating schedules to have a first (zoom) meeting.

Organizing a symposium

What does it take to organize a virtual (or any) symposium? It has to start with a really good idea. In our first organizational meeting, we focused on a theme. Under the broader theme of Staying inspired in uninspiring times, we started to dig in for something narrower but not “only” about the pandemic. Reason being, so much of being an academic is this pendulum of swinging between the highs and lows. Highs can be small and large successes that are few and far. On the other hand, lows are constant and come frequently and in all sizes. Luckily the half life of highs, outlast the many annoying lows. Or, so I’d like to tell myself. Therefore, staying inspired can’t only be about the pandemic and it’s fore-and-aftermath. It has to be about life of a scientist, in general. Because, that.. that is timeless. With that in mind, we came to this theme of an intersection. An intersection of where science, culture and politics meet. I’ll explore on that a lot more in the next post, but for now, the theme quickly became about a triangle w/ three corners …Science, Culture and Politics. And, so it began.

Divide, to conquer.
Our next task was to designate tasks to individuals and make smaller teams to remain organized and focused. I volunteered to take on Media because I find it easy to tweet about science (having done it for 12y) and have a substantial amount of science-network in the NYC area. But, ofcourse, I was also interested in using that network to help find speakers. I got two awesome partners to work alongside for the Media - Bianca and Mericien. Two fantastic humans with very specific skills and darn good taste. So, we started strategizing on when, what and how to get the word out in the subsequent weeks. We had to get the website up, twitter/Insta/LinkedIN set up and most importantly, a nice Logo revamp.

The Logo
For this, I reached out to a dear friend, Elisa Lau (aka Pinkimoon). Elisa is a brilliant illustrator and creative soul with many unbelievable projects stuffed in her portfolio. But, since we didn’t have any money, she agreed to help me out as a personal favor and listen to the theme and came up with some mock ups for the Inspire Symposium logos. I told her I wanted a human sitting at the precipice of thought and innovation pondering how to coerce the impacts of knowledge (Science) and policy (Politics) into the community at large (Society). And, boy, did she deliver! See the logo below!

Getting started
The meat of getting things organized requires the benefit of experience. We had a bunch of veterans from previous meeting, so that helped. Along with Ada, we had Sud (Sudarshan Pinglay). My first impression of Sud was that he was fun, mild mannered with a touch of refreshing team spirit, matured beyond his age. With some great hands on technical side (Nakisha, Deb and Meghan) and the fantastic graduate student duo (Johanna and Julie on the activity team), we were pretty set on what / when/ how to forge ahead. Ofcourse, all of this was meaningless, if we didn’t sort out Speakers.

Finding speakers who fit our theme creeped up at the top of our priority by the end of July. Since we had unanimously approved the theme of Science, Culture & Politics, we already had pretty good ideas on what kinds of people we needed to fill spots. We got pretty lucky and were excited about how warm, encouraging and informative these interactions were. In the next post, I will describe why and how we chose the speakers we did, and how it all turned out. Stay tuned.

Curious case of bradykinins

Like everyone else, I have been thinking quite a lot about the reasons why COVID19 is so much worse for some and can be fully recovered by others with none to mild symptoms.  A variety of clinical strategies are being used to tackle the multi-faceted complexities of Covid19. It has been shown that Spike proteins that decorate the surface of the SARS-CoV-2 virus, bind to the angiotensin converting enzyme 2 for viral entry into the host cell. However, blocking ACE2 has not been that efficient at reducing the progressive phenotype of the disease as reviewed here.

In addition to being a receptor for the Spike proteins, ACE2 functions by converting the inactive decapeptide angiotensin I to octapeptide angiotensin II (Coates D, 2003). When the Sars-CoV-2 virus enters the cell, it infects a variety of cells causing the release of bradykinins. Bradykinins are peptides that are usually converted into inactive metabolites by the angiotensin enzymes. During COVID19, since ACE2 is being used up by Spike for viral entry, bradykinin is no longer converted into an inactive form, thereby resulting in the upregulation of the bradykinin receptors. Increased bradykinin receptor expression can cause a contraction of capillaries, resulting into a number of issues but most importantly a capillary leak and increased inflammation. 

In a 2017 paper by Sodhi et al, it has been shown that attenuation of pulmonary ACE2 activity impairs the inactivation of bradykinin/bkb1r axis that can facilitate LPS-induced neutrophil infiltration as shown in the figure below. There, the authors show that treatment with DX600 (ACE blocker) resulted into increased neutrophil infiltration upon LPS treatment, leading to a heavily inflammatory environment.

 So, do we need to simultaneously block ACE2 (to inhibit viral entry) but also block bradykinins for treatment options for COVID19 patients?

Love in the time of Corona.

Who would’ve thought that our generation(s) will see a pandemic? I think many have shared this idea of writing personal accounts of what / how it feels to go through the pandemic ..wherever you are.

I live in northern nj and work in the city (NYC). here, I just want to log how everyday of the week has felt/been since starting to work from home this month.

each day, I wake up having slept 6-8h and feeling hopeful, refreshed and well-rested. start my day by ritualistic pot of coffee, which used to be limited to weekends pre-covid. now, though, everyday is the same, more or less. so I pour myself a cup of coffee, and start my day by reading emails, then slack, then twitter.

since I wake up pretty early, slack is usually quiet and there aren’t any pressing emails to get to either. twitter, however, is always chock full of information. I quickly scroll through mentions/messages and then go on to look at the feed.. usually stop at the top 50 tweets. during this time, I see dozens of covid19 related tweets with mixtures of paper reviews, technology, policy, stats, so on and so forth. gradually, the sunnyness of my day starts to get... cloudy.

come noon, I have been making serious efforts at being productive. now this can be a variety of things, depending on what day it is. for instance, if it is tuesday morning - I am most likely reading papers for the zoom/JC for immunology. other days, I look through data, write things down. I work a little bit on that OKRs for the month. I go back and forth working on my to-do lists and see what I could squeeze in before afternoon. come afternoon, though, I can’t help myself and go look at the covid19 stats on ny/nj. and then things progress to blues.. well, navy blues.

as the day progresses, i have a meal or two.. i try to listen to some music. maybe even watch some tv. i find ways to distract myself. be it papers, facts, conversations. but, my shoulders feel heavy, my appetite seems sparse. my spirit seem damped. i try to over analyze every sniffle, every random cough, every feeling of heavy heartedness to a symptom. i take my temperature. i log things in a calendar. and i hope for the best.

so, if you are like me. if you never understood anxiety and now are suddenly coping with small or large doses of it for yourself or for your family/friend. if you are someone who doesn’t like to do the touchy feely in your day to day. if you are a biologist and in some ways feel like you have been training your entire life to understand and do this. if you are feeling that heaviness on your shoulders.

then, you are not alone. you are everyone else.

we minimize conversations in public. we wash our hands before touching faces. we observe physical distance, but we keep our hearts and ears open. we write ourselves and others notes of our life because decades from now, when we are healthy, older and possibly greyer, we will remember the time we all pulled through. we will sit in the comfort of our future, flip through these pages from history and time-travel back to a time where humanity was still timeless. and love, even love in the time of Corona.. was ubiquitous and omnipresent.