While I was sad to hear about Alvea’s winddown, you do have a lot to be proud of. As you and others have highlighted, the extreme speed to the clinic for your initial vaccine candidate was unprecedented.
That said, I did want to provide a couple critiques, with the intention of helping guide future EA endeavors in the biotech space. For some context to folks, I’m a mid-career professional working in biologics manufacturing, with experience with both plasmids and vaccines. I also had a number of conversations with Alvea folks at various stages of their clinical development. I’m going to focus here just on the initial push for the 1st candidate, which is the stage I’m most familiar with.
There weren’t enough experienced Alvea team members with significant domain expertise in biotech and vaccines. Your speed to the clinic demonstrated that a team of smart and motivated generalists can achieve operational excellence. You were right to mistrust the industry veterans that said those timelines were impossible*. However, I would argue that there are other areas where industry “common wisdom” was correct, and listening to industry common wisdom would have been beneficial:
Competition from mRNA vaccines. Pfizer had already announced development of an Omicron-specific vaccine in Dec 2021 with a trial starting in January 2022. The original COVID vaccine was approved under an EUA 8-months after initiation of clinical trials. I therefore don’t think it should have been surprising to see an updated anti-Omicron vaccine approved in Sept 2022, 8-months after initiation of that trial.
Low efficacy of plasmid vaccines. I won’t get into the biology here, but plasmids vaccines have generally been shown to have poor efficacy compared to other modalities.
Related, I think the “sprint” mindset made it difficult to recruit experienced professionals. Speaking just for myself, as someone with a mortgage and a child, it’s very difficult for me to justify dropping everything to work on a short term, high-risk project.
Over indexing on the belief that “FDA and big pharma is too slow and EAs could do better”. Generally, FDA and big pharma are (usually) too slow! However, I think as EAs, we need to be realistic about what our marginal contribution can actually be. This is the purpose of assessing for neglectedness in the “impact, neglectedness, tractability” framework. Making COVID vaccines is one of the least neglected cause areas out there, given the billions invested in this space by both industry and the public sector. If I had a main critique of the initial vaccine push, it was along the lines of “how do you think you are going to out-compete Pfizer/Moderna?” (Full-disclosure, I’m an ex-Pfizer employee myself). This also plays into why domain expertise is useful. In a highly crowded space, it’s particularly important to understand the competition.
Anyway, these critiques still don’t take away from what you accomplished. I would particularly love to hear more at some point about how you managed to get your external partners to meet your timelines, for very self-interested reasons!
* I do want to say that this was not a universal sentiment among industry veterans. Checking back to our initial emails, at least from a manufacturing perspective I never argued that your goals were unachievable. This plays a bit into my third critique as well.
1. I generally agree with your point on experience (wrote this in my reflection as well). Your specific examples do not track for me though. We knew that an mRNA omicron vaccine was coming. The point was, that no booster for LMICs was in the pipeline and mRNA vaccines were basically inaccessible in most parts of the world. We also were very aware of the low efficacy of plasmid vaccines but boosting with plasmid vaccines in the context of a new variant was something not tested before and the hypothesis was that it might be sufficient for significant additional protection against Omicron. The latter was certainly the riskiest bet but a valid scientific hypothesis worth testing.
2. It seems a general problem of start-ups that they are not as attractive to settled individuals. I can see how the sprint mentality might have contributed here. Luckily we eventually were able to attract a lot of mid-career professionals. And some people really appreciated the initial 3-month sprint plan, i.e. not having to commit to something in the long term.
3. Again, as far as I could tell no one was working on a COVID-19 booster optimized for LMICs. At the time there were valid concerns that Omicron might cause a lot of trouble for the world. How did we planned to outcompete Pfizer/Moderna? We didn’t plan to compete with them on their target audience, but have a vaccine that is shelf stable for 6-months at room temperature (which we achieved), that could be potentially be manufactured nationally, and hopefully sufficiently effective. I think it is worth pointing out that despite not being as amazing as mRNA vaccines, AZ for instance seemed to have saved the most lives during the pandemic because it was more accessible to the global south: https://www.economist.com/graphic-detail/2022/07/13/which-covid-19-vaccine-saved-the-most-lives-in-2021
Thanks for the thoughtful response Max, and I appreciated your separate write-up on this subject.
I do want to highlight though that in his write-up, Kyle listed the improved regulatory environment for updated mRNA vaccines as a reason why Alvea decides not to proceed with your first vaccine candidate. That’s really what I was addressing with my comment.
As to the second point about lack of efficacy for plasmid vaccines, I think there were different opinions on this within Alvea. One high ranking person I spoke to gave me the opinion that poor performance of a competitor COVID plasmid vaccine was due to competitor incompetence rather than an issue with plasmid vaccines themselves. That sort of comment is why I mentioned my concern that there may of been a degree of contempt among some in Alvea for big pharma.
Totally agree as to the “practical” efficacy of the adenovirus vaccines though!
While I was sad to hear about Alvea’s winddown, you do have a lot to be proud of. As you and others have highlighted, the extreme speed to the clinic for your initial vaccine candidate was unprecedented.
That said, I did want to provide a couple critiques, with the intention of helping guide future EA endeavors in the biotech space. For some context to folks, I’m a mid-career professional working in biologics manufacturing, with experience with both plasmids and vaccines. I also had a number of conversations with Alvea folks at various stages of their clinical development. I’m going to focus here just on the initial push for the 1st candidate, which is the stage I’m most familiar with.
There weren’t enough experienced Alvea team members with significant domain expertise in biotech and vaccines. Your speed to the clinic demonstrated that a team of smart and motivated generalists can achieve operational excellence. You were right to mistrust the industry veterans that said those timelines were impossible*. However, I would argue that there are other areas where industry “common wisdom” was correct, and listening to industry common wisdom would have been beneficial:
Competition from mRNA vaccines. Pfizer had already announced development of an Omicron-specific vaccine in Dec 2021 with a trial starting in January 2022. The original COVID vaccine was approved under an EUA 8-months after initiation of clinical trials. I therefore don’t think it should have been surprising to see an updated anti-Omicron vaccine approved in Sept 2022, 8-months after initiation of that trial.
Low efficacy of plasmid vaccines. I won’t get into the biology here, but plasmids vaccines have generally been shown to have poor efficacy compared to other modalities.
Related, I think the “sprint” mindset made it difficult to recruit experienced professionals. Speaking just for myself, as someone with a mortgage and a child, it’s very difficult for me to justify dropping everything to work on a short term, high-risk project.
Over indexing on the belief that “FDA and big pharma is too slow and EAs could do better”. Generally, FDA and big pharma are (usually) too slow! However, I think as EAs, we need to be realistic about what our marginal contribution can actually be. This is the purpose of assessing for neglectedness in the “impact, neglectedness, tractability” framework. Making COVID vaccines is one of the least neglected cause areas out there, given the billions invested in this space by both industry and the public sector. If I had a main critique of the initial vaccine push, it was along the lines of “how do you think you are going to out-compete Pfizer/Moderna?” (Full-disclosure, I’m an ex-Pfizer employee myself). This also plays into why domain expertise is useful. In a highly crowded space, it’s particularly important to understand the competition.
Anyway, these critiques still don’t take away from what you accomplished. I would particularly love to hear more at some point about how you managed to get your external partners to meet your timelines, for very self-interested reasons!
* I do want to say that this was not a universal sentiment among industry veterans. Checking back to our initial emails, at least from a manufacturing perspective I never argued that your goals were unachievable. This plays a bit into my third critique as well.
Hey Matt,
thanks for your thoughts!
1. I generally agree with your point on experience (wrote this in my reflection as well). Your specific examples do not track for me though. We knew that an mRNA omicron vaccine was coming. The point was, that no booster for LMICs was in the pipeline and mRNA vaccines were basically inaccessible in most parts of the world. We also were very aware of the low efficacy of plasmid vaccines but boosting with plasmid vaccines in the context of a new variant was something not tested before and the hypothesis was that it might be sufficient for significant additional protection against Omicron. The latter was certainly the riskiest bet but a valid scientific hypothesis worth testing.
2. It seems a general problem of start-ups that they are not as attractive to settled individuals. I can see how the sprint mentality might have contributed here. Luckily we eventually were able to attract a lot of mid-career professionals. And some people really appreciated the initial 3-month sprint plan, i.e. not having to commit to something in the long term.
3. Again, as far as I could tell no one was working on a COVID-19 booster optimized for LMICs. At the time there were valid concerns that Omicron might cause a lot of trouble for the world. How did we planned to outcompete Pfizer/Moderna? We didn’t plan to compete with them on their target audience, but have a vaccine that is shelf stable for 6-months at room temperature (which we achieved), that could be potentially be manufactured nationally, and hopefully sufficiently effective. I think it is worth pointing out that despite not being as amazing as mRNA vaccines, AZ for instance seemed to have saved the most lives during the pandemic because it was more accessible to the global south: https://www.economist.com/graphic-detail/2022/07/13/which-covid-19-vaccine-saved-the-most-lives-in-2021
Thanks for the thoughtful response Max, and I appreciated your separate write-up on this subject.
I do want to highlight though that in his write-up, Kyle listed the improved regulatory environment for updated mRNA vaccines as a reason why Alvea decides not to proceed with your first vaccine candidate. That’s really what I was addressing with my comment.
As to the second point about lack of efficacy for plasmid vaccines, I think there were different opinions on this within Alvea. One high ranking person I spoke to gave me the opinion that poor performance of a competitor COVID plasmid vaccine was due to competitor incompetence rather than an issue with plasmid vaccines themselves. That sort of comment is why I mentioned my concern that there may of been a degree of contempt among some in Alvea for big pharma.
Totally agree as to the “practical” efficacy of the adenovirus vaccines though!