Viene post largo, pero interesante que creo que resume los problemas técnicos que han tenido y las dudas que pudiera haber.
La conclusión es que creo que sí que tienen todos los problemas solucionados (salvo quizás Texas, pero independientes del proceso y escalado en el resto) y ningún impedimento para que lleguen las aprobaciones. Y sabéis que no soy un optimista irredento y me gusta ser crítico y analizar bien las posibilidades.
Todo esto es un resumen de lo que he estado leyendo por Twitter, e IV, principalmente en las discusiones de red y otros con experiencia en el tema.
IgG y diferencia NAbs en presentaciones:
No hemos visto los datos del estudio comparativo, pero NVAX produce menos que las mRNA. Esto no quiere decir que sea menos efectiva, ya que los NAbs son en principio similares a los de MRNA que es la que más genera. Estaría muy bien ver los datos y comprobar que es así. Podría ser más parecida a PFE en cuanto a NAbs y si fuera inferior en ese estudio concreto, podría tratarse de un lote de antes de solucionar los problemas de consistencia de producción.
De todas maneras dos fases 3 independientes con diferente producto han verificado lo eficaz que es la vacuna y es el argumento de mayor peso para abogar por esta explicación. Que enlaza con la diferencia de NAbs desde la fase 1 hasta la 3 que se ha visto en los datos mostrados por la compañía. Muy probablemente es el método de evaluación y medición ha cambiado, es diferente, o las condiciones fueron distintas. Pequeñas variaciones en temperatura, tiempo y demás pueden variar enormemente el resultado. Pero esto es una incógnita aún (el por qué esa diferencia en los datos mostrados por la compañía, que no ha explicado ni ningún analista preguntado).
Sobre la pureza:
Básicamente que lo del 90% no es una exigencia en ningún sitio, que más del 80% es el requisito normalmente. Además, en este caso las impurezas de la vacuna son conocidas y no suponen un problema (aunque obviamente cuanto más pureza más cantidad de antígeno cercana a esos 5ug). Aparte que el estudio de fase 3 se hizo a partir de los datos del biorreactor de 2000l con el que la FDA estaba conforme.
Red apunta que:
Flu vaccines are not 80% I can assure you. Some are better than others but 70% is not uncommon and extraneous materials are egg proteins.
GlobalHealth en IV:
https://www.investorvillage.com/smbd.asp?mb=193&mn=147068&pt=msg&mid=22533831Related to the Politico article, I just did some research to find if vaccines in general, or even recombinant protein vaccines, are as a rule actually required to have greater than 90% purity levels. I found this website of a company that specializes in purification of protein vaccines and protein drugs, and it clearly says that for Mass spectrometry vaccines, which include VLP vaccines and recombinant protein vaccines, they only need to be greater than 80%.
So it appears that in addition to the many other inaccuracies in the Politico article, that it was also inaccurate about its statement that all vaccines had to be 90% pure. Note that the purity percentage basically refers to what percentage of the vaccine contains only the full length spike proteins that fight infections. As others have noted, making a protein vaccine creates plenty of harmless, inactive byproducts and also some spike proteins that are not full length. They remove a good amount of this so that there is a relatively high concentration of the full length proteins. It is physically impossible to remove all of it.
The website also has a free 100 page technical guide to purification. It says that what matters is whether or not the 20% that is not the full length protein… is harmless inactive material or is biologically active material that would produce a problematic effect in a person. As a point of reference, while I never did cocaine myself, I have heard other people including in many movies and TV shows talk about cocaine that is high purity… referring to the percentage of it that is cocaine versus the percentage that is normally inactive harmless material.
Of course cocaine producers could potentially put some active harmful material in along with the cocaine, but they would never get any repeat business if they did that. The politico article made it sound like because the Novavax vaccine has Impurities in it, it means there is a sizable likelihood that there are dangerous impurities in it. I was pretty sure that’s not the case or else they would not have filed with the WHO and the three countries. Now this presentation you link to states that the only impurity is a known harmless one that is natural to the process.
The two things above are just two of many inaccuracies in the politico article. As an example of how misinformation spreads, I saw two other articles referring to the politico report and they also said that 90% purity was required.
In other words, the other articles pointed out that the 70% claim came from an unnamed source. But they did not say the 90% requirement for allrequirement for all vaccines also came from an unnamed source. Instead they stated that 90% part as if it was a definite fact.
The reason they did this is because the politico report also did not bother to say that the 90% claim came from one of its anonymous sources. Politico stated it as if it were a fact that they had independently looked up and verified themselves. I’m pretty sure the 90% claim came from one of their unnamed sources, but they didn’t bother to note that. They should have noted that so that readers could know it’s not a fact and might be incorrect if the unnamed source had a dubious motivation.
So now when other publications view their article, they assume it is a fact and so they report it as a fact. Numerous people will come across these various articles in the future and think it is a fact and go around quoting it as a fact. Even when they are looking at other vaccines, and they Google to find information on required purity levels, many of them will come across these inaccurate reports and think that all vaccines being required to have 90% purity is a fact.
Here is the link to the company that specializes in purification of protein vaccines and protein drugs. The second graphic on this page says that only 80% purity is required…
https://
www.cytivalifesciences.com/en/us/solutions/protein-research/knowledge-center/protein-purification-methods/how-to-combine-chromatography-techniques
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Aparte, me he estado leyendo los documentos de EMA y previo a registrar toda la documentación tiene que estar muy claro todos estos puntos y la compañía sabe lo que tiene que entregar y la calidad que tiene que alcanzar. Creo que las opciones de que no se cumpla en cuanto a la pureza son mínimas y las críticas que han vertido por ahí son por gente que no conoce cómo funciona el tema o que van cortos (o largos en competidores).
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Probemas con la FDA:
Un post interesante sobre esto también y con las dudas que ha podido tener la FDA:
Básicamente los problemas han venido en la transferencia de tecnología y al compartir información de estos sitios en los que el proceso no estaba aún bien ajustado con la FDA por motivos de tiempo. Lo que he comentado de que han intentado abarcar mucho y
fueron demasiado ambiciosos, un pecado del pasado también. Y por qué pienso que la directiva es incompetente en este sentido.
Red, as you are well aware, and, I agree the spec that was the official foundation for filing was the 2000L batch work, scale up of production is the key, not the lab nor pilot scale work, which form the development database. Specs are expected to be somewhat fluid until there is sufficient statistical basis for firm specs, which comes with volume work and scientific understanding of the dynamics of the process and formulation. In this case I think there was sufficient time and batches to develop a high degree of confidence in their purity spec, though I will again say these small companies just do not have the firepower to study their processes like the bigger boys do in supportive studies for data generation. I believe the analytical problems for NVAX occurred during tech transfers.
I have never seen a company undertake this bold of a strategy.
They attempted to manage several (international) tech transfers while still in late stage process development it appears. Pfizer and Moderna took a much more focused approach and I think it cost NVAX in the end. I think FDA may have seen some results variation between batches produced and tested during transfers, which normally would not be a huge issue as FDA typically looks at US registration data for the US market. But, under EUA and with time so compressed I believe data from these transfers entered the equation unfortunately. And, if there was a higher than desired level of analytical variation in a key assay, which could be the case, especially when there is insufficient time and experience with the method, the results could suffer in 'consistency'. It was a bold strategy, which should still pay dividends long term, but, they gambled and screwed up the short term.
It still appears NVAX is there now, ready to compete with the big boys. I just hope they can find a good partner sooner than later, to help them going forward with all they have to manage, it is only beginning now. I am hopeful the world will experience NVAX very soon because people I know are getting tired of hearing me mention they are coming with the best vaccine.
