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My ex-colleagues just posted the official Alvea winddown announcement as well as Kyle’s reflections on our activities over the past 1.5 years. I wanted to complement these posts with some additional comments.

Publication of the South Africa Trial Results

Our academic publication of the South Africa Trial results are currently under review, but you can see the submitted manuscript here. We also published the complete data-set as well as the full study report. While Kyle describes our efficacy results correctly as underwhelming (btw - the Janssen comparator as well), the trial made several important scientific contributions. To our knowledge this study is the first time where

  1. A naked DNA based SARS-CoV-2 booster candidate was studied in preimmunized humans (with ~80% having hybrid immunity from previous infections).
  2. Unusually high doses of up to 8 mg DNA plasmid were administered intradermally / subcutaneously during a single visit.
  3. A SARS-CoV-2 vaccine candidate was compared during its first Phase-1 safety study against a licensed comparator (Janssen’s Ad26.COV2.S). (Sidenote: it is insane that this seems to be the only COVID-19 trial that managed to get an comparator)

Lessons learned

In addition to Kyle's list, here are some more I'd like to point out:

  1. Experience matters: Alvea matured substantially over time. From my perspective, many important internal operations mistakes could have been prevented if there had been more experience in the team earlier on. Same for research decisions and other mistakes we made. Sometimes you really want this person who has 4,000+ h of work experience and not 40h of research experience. Maybe even often.
  2. You can hire people remotely: It is very common for orgs to be hesitant to hire internationally. I myself would not have been able to work for Alvea if Grigory wouldn’t have been creative about contracting and working with Employer of Records to employ ~50% of the 45 person team. I claim that organizations are missing out on top talent if they are only fishing in their country.
  3. We had kick-ass values I am still identifying with (shoutout to Eric for shaping our company culture with those)
    1. Ownership: We take personal responsibility for achieving exceptional results. We draw energy from doing the “impossible.”
    2. Agility: We move with speed and flexibility in the face of constant uncertainty.
    3. Truthseeking: We chase the truth, especially when it requires courage. We experiment to change our minds quickly.
    4. Care: We have each other’s back. Our mutual support sparks our growth as a team and our impact in the world.
  4. Medical countermeasures matter: I get the vibes in EA that people are not excited about medical countermeasures / their deployment. I’d like to challenge that. Ambulances, firefighters, and police take less than 15 minutes to arrive at an emergency scene. Starting a clinical trial 100d? Humanity needs an equivalent pharmaceutical preparedness and response ability to stop pandemics in their tracks. For instance, I would like to see work on a 100h response plan (in addition to the 100d CEPI timeline) to an outbreak using candidate vaccines and ultra-rapid ring-vaccination trials. So consider PanopliaLabs when allocating your donations this year.

Drug Development Explainer Series

I just cross posted an explainer series on drug development from my website I wrote up with James Smith and Kirsten Angeles. I argue it captures most of the insights on the pharma landscape we made at Alvea and recommend it to everyone who wants to get a comprehensive overview of how drugs are made.

One article in the series describes some of the core cultural and operational activities that allowed Alvea to execute that quickly. For convenience, I copy paste this part here:

Understand/verify industry best-practices.

Alvea spent a lot of time and effort to educate themselves about how to best navigate a very ambitious drug development program. Part of what motivated the authors of this article to write it was not finding a comprehensive end-to-end overview of the essential parts of drug development that could be given to staff members without a history in drug development. Many ways get you there including: reading the GxP guidelines; reading regulatory documents of jurisdictions; investigating documents of other clinical trials; talking to a variety of consultants or doing training programs. Don’t be afraid to ask dumb questionsIt turns out that you’ll end up getting a non-trivial amount of contradicting evidence and resolving is on you - the final responsibility always resides with the sponsor. Combine understanding/verifying what you ought to be doing with an unwavering focus on a primary goal (“Submit our injectable Alveavax-v1.2 clinical trial application to South Africa for conditional approval before March 18th 2022, as long as GLP BA2 studies show positive results.”), relentless work and quick turnarounds, and you are kind of set up for success. For many at the company it was the closest to lived operational excellence they had experienced yet.

Determine your jurisdiction and exact specification

While ICH provides an exceptional improvement in terms of harmonisation across countries’ drug development regulation, and for vaccines in particular many refer to the WHO guidelines, countries differ in nuances that eventually matter. Alvea scanned the world and deeply considered at least 10 different options to find a jurisdiction that provided the right mix of right target population, regulatory clarity, fast timelines and reputable regulators. The top candidates for a Phase 1 study ended up being Australia, South Africa, and Canada, and the decision was made to proceed with South Africa.

Once Alvea knew the target jursidiction, processes could be optimised. The exact specification kick off all the downstream processes: animal testing (which, how many, how long, etc.), GMP material (how stable, what exact GMP specification, etc), submission criteria (timelines for review cycles, do you need to have all the data for submission or can you provide certain documents such as drug stability data later). CROs often like to claim that they can run trials anywhere, but sponsors benefit heavily from local expertise gained by past trial run with the same study sites, ethic boards, laboratories and supply depots. Going with a locally experienced CRO and having exceptionally high standards for the CRO’s project manager was key to the success of the study.

Find, evaluate, and parallelize vendors (or do it yourself if you can).

For manufacturing, animal testing, regulatory application, trial setup, and all the respective subdomains highly specialised suppliers or contractors exist. Towards the goal of conducting the clinical trial, all of them constitute single points of failures. Alvea was very concerned about this and therefore followed a couple of strategies: 

  1. Whenever you can reliably do it yourself, you should. Communication across orgs is harder and in most scenarios you don’t know how relentless another party will ensure that they deliver the right results on time, even if it means more hours, a different process, etc. Examples include inhousing initial steps for creating starting material for manufacturing yourself or designing the clinical trial protocol. 
  2. If you can afford it, parallelize vendors. Alvea had to rely on contractors for manufacturing, animal testing, and parts of clinical trial setup. For all of them at least initially multiple parties were hired and thoroughly evaluated. The trial was also submitted to multiple jurisdictions. 
  3. Build a quality management system and audit contractors. This is not regulation slowing you down, but regulation saving your a** from future disasters. 
  4. Be able and willing to part from vendors. Alvea was dissatisfied with the performance of multiple CROs and even while running the trial decided to stop the collaboration and find new partners or in-house the activity. 
  5. Build partnerships with contractors that deliver exceptional results. 

Finally: Shoutout to the team and funders

There is no page where all Alveans are listed, but I still wanted to link to two pages on archive.org that acknowledge (most of) the team members that made this possible:



I heard again and again ex-colleagues saying “I’m spoiled for life - this team was special”. I agree and am proud to have had the chance to collaborate with all of you. #meta-gratitudes

I also want to acknowledge our advisors and the funders who were willing to take a bet. While eventually not successful, I very much hope that the Alvea story inspires funders to go for similar projects in the future (which obviously should address the shortcomings of Alvea as a project and organization). Something truly special is unlocked when you enable talent with generous funding to obsess about ambitious ways of doing good in the world.





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Thank you so much for your hard work, frank announcement, and detailed retrospectives!

One thing I'm curious about as a layman: Does your vaccine work?

If I understand your posts correctly[1], the claim from the Phase 1 trial is that it doesn't increase antibodies (an intermediate proxy for increased immunity) more than the J&J vaccine comparator. However, I still don't know which of the following hypotheses are true:

  1. Your vaccine works (in the sense of conferring partial immunity to ongoing variants of SARS-COV-2), but its effectiveness level is not statistically distinguishable from J&J and other existing vaccines, so not worth further R&D in.
  2. Your vaccine does not confer immunity.

For example, have you done followup checkins to compare the treatment group's rate of infection to the control group?

Secondly, was the result of your vaccine trial an expected outcome?

eg, going in, was the team's opinion more like

  • "we think in most worlds this vaccine won't work, but we wanted to make a low-proabbility high-upside bid in a novel product?" or was it more like:
  • "we think this vaccine probably will work, and we'd be sad if it doesn't?"

While I hate to "punish" your level of transparency by demanding more answers, I think understanding your internal models, levels of surprise, and how the team internally thought about setbacks and pivots can be useful for future EA organizations attempting similar ambitious real-world projects. 

Anyway, thank you again for your hard work and detailed reflections!

  1. ^

    So far, I've read your retrospective, the official announcement, Kyle Fish's reflection, and the linked Google Doc preprint. I haven't read anything else about Alvea, please feel free to let me know if I'm missing any key links.

Executive summary: Despite efficacy results falling short of expectations, the ex-Alvea employee highlights important scientific contributions and valuable lessons from the company's bold effort to rapidly develop a DNA vaccine during the pandemic.

Key points:

  1. The South Africa trial made scientific contributions like testing unusually high DNA vaccine doses and including a licensed comparator.
  2. Key lessons include the value of experience, remote hiring, medical countermeasures, and drug development best practices.
  3. The culture and team were exceptional in relentlessly pursuing ambitious goals.
  4. Partnerships and parallelizing vendors were crucial to move quickly.
  5. Quality management systems help avoid disasters.
  6. Funders enabling talented teams to obsessively pursue good is inspirational.


This comment was auto-generated by the EA Forum Team. Feel free to point out issues with this summary by replying to the comment, and contact us if you have feedback.

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