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One of the world’s leading vaccine manufacturers has suffered a major setback in its work to produce a Covid-19 vaccine. The problem will push the timeline for deployment of Sanofi Pasteur’s vaccine — if it is approved — from the first half of 2021 into the second half of the year, the company said Friday.

The news is not just disappointing for Sanofi and its development partner, GlaxoSmithKline, which is providing an adjuvant used in the vaccine. The companies have contracts with multiple countries, including the United States and Britain, as well as the European Union.

Sanofi had hoped to start a Phase 3 trial of the vaccine this month and had projected it could produce 100 million doses of vaccine in 2020, and 1 billion doses in 2021.

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The problem relates to inadequate results in older adults in Sanofi’s Phase 1/2 trial, which the company traced back to an inadequate formulation of their vaccine, Su-Peing Ng, global medical head for Sanofi Vaccines, told STAT in an interview.

Ng said both Sanofi and GSK are committed to continuing work on the vaccine, and plan to begin a Phase 2b trial in February.

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“We’re disappointed that there is a delay,” she said. “I think, though, that we’re encouraged that we have enough information, enough of the results from preclinical and clinical [studies] to tell us that we have a path forward. We need to optimize this formulation.”

In effect, participants in the trial received too little vaccine. While the too-small dose generated adequate levels of neutralizing antibodies in adults aged 18 to 49 in the trial, adults 60 and older generated lower levels of neutralizing antibodies than are seen in the blood of people who have recovered from Covid-19 infection, Ng said.

Perplexed by the findings, the company set out to figure out why the vaccine underperformed. It discovered two commercial reagents used to measure how much antigen — active vaccine — was included in each dose were giving false readings. In fact, Ng said, the concentration of the antigen “was insufficient.”

A revised formulation, tested recently in non-human primates, showed the vaccine prevented damage in the lungs, which is what triggers severe Covid disease in people, and led to rapid clearance of the virus.

The vaccine’s path will be more challenging because of this delay; the Covid vaccine landscape is changing daily and placebo-controlled trials may not be feasible for much longer, with the first vaccines soon to be deployed. If people know they may soon have access to an authorized vaccine, there is less motivation to enroll in a trial where they might get a placebo.

Sanofi knows this and is proposing to the Food and Drug Administration that its Phase 2b trial compare its vaccine to one that is already authorized, not a placebo.

“To continue to provide confidence that we’re going to have a vaccine that meets the expected standard of care, we propose the comparison with an authorized Covid-19 vaccine instead of placebo control,” Ng said.

That would set a very high bar for the Sanofi vaccine. Pfizer and Moderna, the front-runners in the vaccine race, have reported vaccine efficacy of about 95% in their Phase 3 trials. If the Sanofi vaccine doesn’t reach that level of efficacy, can it be brought to market, STAT asked Ng.

“That will be up to the regulators,” she said, adding that “for the public to be confident in the choice of a vaccine, it would have to be pretty close to what’s been established now.”

The Sanofi vaccine would have one advantage compared to the Pfizer and Moderna vaccines: It wouldn’t require ultracold storage and could instead be kept in standard refrigerators, making it easier to distribute.

Pfizer and Moderna are poised to receive emergency use authorizations from the FDA this month — an FDA advisory panel endorsed the Pfizer shot on Thursday — and vaccine rollout in the United States is expected to begin within days of the FDA’s green light. The Phase 3 trial for Johnson & Johnson’s vaccine — the only one-dose vaccine currently in clinical trials in the U.S. — is about to finish enrollment; if it is effective, it could get an EUA in the first quarter of 2021.

The Sanofi vaccine is made with an approach the company uses for one of its flu vaccines, Flublok. That in theory is an advantage; the FDA knows how this vaccine system works. It’s called a recombinant protein vaccine, with the spike protein of the SARS-CoV-2 virus, which causes Covid-19, generated in insect cells.

Sanofi is also developing a second vaccine, a messenger RNA vaccine, like the Pfizer and Moderna shots. For this project, it is collaborating with Translate Bio, a Lexington, Mass.-based biotech. Clinical trials for that vaccine have not yet begun.

  • Why wouldn’t Sanofi use this to their advantage and get an approval for the 18-49 market, which is the largest patient subgroup of covid positive results (including those working in nursing homes, on cruise ships, hospitals, teaching positions, and food processing plants) and continue their efforts separately for the over 60 patients. What would they not take the opportunity to apply a higher level of personalized medicine to the standard one-size fits all vaccine manufacturing paradigm. Wouldn’t it result in less adverse reactions in the 18-49 group to keep the lower antigen levels and only increase them for the sake of response in the over 60’s as necessary?

  • We want ivermectin! Cheap & effective. Proven results. Economy, schools, restaurants could open. No one will have covid or recover. No death from Covid.

  • Why do we need a Vaccine to begin with… they are only as good as the recent viral strain and they only last 4-8 months.
    Why not perfect a TREATMENT option to be used on-demand? Let’s redirect those billions of dollars and look at Ivermectin or combine it with something else. Some options that ACTUAL work on reducing the inflammation damage of the Covid virus.

    BRILACIDIN is one of the few drugs targeting COVID-19 as a treatment an Prophylactic that has been tested in human trials (a total of 8 times) for other clinical indications, providing an established safety and efficacy database on over 460 subjects, thereby potentially enabling it to rapidly help address the novel coronavirus crisis. Ongoing laboratory testing conducted at a U.S. Regional Biocontainment Laboratory (RBL), and at a Public Health Research Institute (PHRI), supports Brilacidin’s antiviral ability to safely inhibit SARS-CoV-2 in both human and animal cell lines.
    A molecular screening study of 11,552 compounds also supports Brilacidin as a promising novel coronavirus treatment.
    Seems that government and deep pocket companies are holding the world at bay during the times of a given pandemic. My two cents.

    • Vaccines prevent or reduce morbidity and are far more cost effective than treatments. Both are being developed. It’s not either/or. Furthermore, patients are infectious several days before showing symptoms, so treatment will not slow the pandemic as vaccines will.

    • Brilacidin – is an antibiotic. Whose main purpose is to fight infections of bacteria not viruses. Viruses are not bacteria, viruses are not single celled organisms.

      Worse yet, using experimental antibiotics for non-bacterial infections is going to cause bacterial resistance in surrounding bacteria to those very antibiotics that will be needed for other diseases(caused by bacteria). Which is another future potential crisis of a world without functional antibiotics. And people need to use fewer antibiotics – not more!

  • I have questions I have seen zero answers to, regarding the Mrna Covid vaccines: 1. Which cells end up with the changed instructions? Do they know? 2. Do those cells eventually die, or do they divide and then new cells continue with the virus particle/protein production? 3. Are there long term immunological issues? 4. What happens if a cell with these instructions becomes cancerous?
    Until there are GOOD answers to these questions, I will NOT take an Mrna vaccine. I’d rather travel to where there is a vaccine with proven technology available and get that, then get what’s being pushed at us by companies more interested in cheaper faster rather than our well-being.

    • The mRNA in the vaccines does not get permanently added (ie, integrated) to your DNA. In the body, mRNA (including synthetic mRNA as in the vaccines) degrades fairly quickly (hours typically) via normal processes.

      Human cells don’t reproduce the way you are suggesting. Cells that are already differentiated (like muscle cells) don’t undergo cell division to make new ones.

      I’m not sure anyone can really give you confidence that there are no long-term immunological consequences, but mRNA (and other nucleic acid) based drugs have been used for some time and these haven’t been common issues.

      Cancer would be a concern if the mRNA was integrated into your genome, but that’s not what happens with these vaccines.

    • I always strongly suggest that people perform their due diligence and consider what the risk versus reward aspect of any treatment option is. I know for a fact, given a study involving individuals in my medical and age category, that this virus poses less of a risk to me than the unknown aspects of this vaccine. Your own situation may be different than mine, however, so I won’t try and tell you one way or the other how to proceed, but I would certainly not be the first in line either way if you find that to be a feasible option.

  • It is already known that 2 licensed vaccines based on recombinant proteins from insect cells are not as immunogenic as recombinant protein made in yeast or virus grown in eggs or mammalian cells (Flublok vs egg based flu vaccines and Cervarix vs Gardasil). Including a potent adjuvants, such as MPL and QS21 to make this protein immunogenic may have serious safety issues for a disease, which is mainly due to hyper innate and adaptive immune response. Please see my recent article discussing challenges with various platforms used for COVID-19 vaccine at the link below.
    https://www.researchgate.net/publication/344777956_Challenges_and_Risks_in_Development_and_Manufacture_of_COVID-19_Vaccine?_sg=BfUWaZEd3VNtKkb-mCIMIvRzG8_wYaPhfhAhPXtcgZCRclu7Ox6wfHCOfSKlX78bBI4TtmyBoWlvTxgz7_MHWIRRHNDyBk6qxUXSfjIK.bEtcjaMcc0JuZOz6ISCz9Aj6jgNLBTdb-89Lkr2dihz9J2S9PzuASaiZmxHMA_0sFcErtn0lDUs6wz-NofdeGg

  • It appears to me that there’s a fine balance between efficacy and side effects. Higher doses such as Pfizer and Moderna are very effective however suffer from significant side effect issues. Sanofi unfortunately goes to the other end a bit too far due to its own blunders (shoutout to Oxford/Astrazeneca). In between, Sinopharm and Sinovac vaccines seem to be more balanced. For different group of people, I suppose each vaccine, including Sanofi’s, has some merits. However, in the race of time, Sanofi have regretfully fallen further behind. For the best interests of human kind, Sanofi, Astra and their governments should (swallow their bitterness or pride) stop reinventing wheels and instead give front runners support!

    • I wouldn’t take a Chinese vaccine for this virus. I seriously doubt the integrity of their data especially on the research side.

    • What is is about the “Pfizer” (actually BioNTech) vaccine that you consider “significant side effect issues”? I don’t see anything in the study data that would ring major alarm bells.

    • Well there were several(numbers differ) nurses that received a single dose of the Pfizer vaccine(the 1st day of vaccinations) in the UK that seemed to have suffered significant allergic reactions(that needed medical treatment). Which required the UK government to issue special instructions for certain people(of all ages) with allergies to medications to avoid the Pfizer vaccine, even if normally healthy.

    • To be fair to the Chinese companies(Sinopharm and Sinovac) – they are conducting trials in other countries and with other racial and ethnic groups.

      Brazil, Chile, Indonesia, Pakistan, Turkey, the trial in the United Arab Emirates was apparently open to citizens of the US, EU, and other other countries. So the results are not limited to China. China is already vaccinating its citizens who travel to other countries and they are not seeing the “waves” of infections other countries(Europe and North America) are, so obviously something is working.

      Brazil, Indonesia, and Pakistan are some of the world’s most populated countries, combine any 2 and you probably have more people than the US. It is well known that COVID is having a catastrophic effect on Brazil because its medical infrastructure is more or less developed. In the 3rd world conditions of Indonesia and Pakistan the situation may be worse than the “official” data claims. And these countries with their climates are unlikely to receive the sub-zero Pfizer vaccine or be able to properly store it. So a simpler Chinese vaccine for them is just what they need.

      Chinese vaccines are very unlikely to end up in the US unless they are license produced in US facilities, and if so would be made to US standards. But the CDC is against using whole coronaviruses in vaccines(something to do with experiments showing immune disease enhancement with previous SARS viruses) on US soil. And most Chinese vaccines use whole coronaviruses as a component.

  • Why would Pfizer create a vaccine at -80 when other companies are at a much lower temperature for their vaccine? They have a temperature problem that other companies don’t. Why would they do that? And why would the USA buy this vaccine if there may be possibility of spoilage.

    This question is about two shots. Why do the vaccines require two shots? What happens if a person just has one shot? Is one still protected to some degree? Why not give everyone the first shot then give everyone the second shot? That way everyone is getting some safety against the virus asap? Could you explain that? Thanks.

    • Mike,
      The storage and dosage requirements of Pfizer’s vaccine are data-driven, not design factors. The primary focus in R&D is getting an effective vaccine. Once you show it works, then you find out how stable it is at different temperatures and how to optimize dosing. These inconveniences are the price for the fastest thing that works.

      -CK
      Source: I am an R&D scientist for a vaccine company

    • Pfizer created jack sh*t. It’s not their vaccine. It’s BioNTech’s. Pfizer came in for the clinical trials and the distribution. And storage at -70C is standard procedure for storing RNA, which is easily degraded at higher temperatures because RNA-digesting enzymes are practically everywhere humans touch. If Moderna has found a way to stabilize the RNA, kudos to them, but that likely involves additional adjuvants in the vaccine that could otherwise be done without.

      As for the two shots, it’s standard procedure for many vaccines to give several shots for full effectiveness. One shot does provide some protection, but not in everyone and not reliably. In many people, the antibody count will not be high enough to protect them. The data from the trial for the BioNTech/Pfizer vaccine shows that after the first shot, efficacy was only around 52%.

    • Fantastic questions Mike. I can’t speak to the reasons for the -80 requirements for the Pfizer/BioNTech vaccine. In response to your latter questions, there has been a lot of interesting discussion happening on twitter. Walid Gellad has started a conversation about this on twitter, you may find it helpful to follow him. That conversation is here: https://twitter.com/walidgellad/status/1337126791249600513

    • I suspect they skipped efforts to develop a more stable formulation in order to get the vaccine out sooner. The fact they will be first to win approval is evidence of that. they will be following up with a more stable formulation, especially since Moderna has already done that and there are other vaccines in the pipeline that can be stored under normal refrigeration.

    • I don’t know if you ever saw the sci-fi movie “Jurassic Park”, but the Pfizer vaccine is using a somewhat similar genetic technology concept as the fictional scientists in that movie.

      They modified reptile DNA in Ostrich eggs to recreate dinosaur embryos, from pieces of genetic code they synthesized, to mimic dinosaur DNA when combined with reptile genes in the eggs. The messenger-RNA process used by Pfizer/BioNTech(and Moderna) in its vaccine is doing something similar, but change eggs to cells in the human body. It is mimicking a COVID infection in the human body by stimulating the cells of the body to create antibodies and build up immune defenses. Viruses normally use their genetic code to attack a human body.

      But this process takes time, like a serious infection, it takes days before the body builds up its defense and you feel healthy again. Sometimes though this is not enough to stimulate immunity. So several weeks later(when the effects of the 1st shot wear off) the body must again go through another “simulated” infection(receive the 2nd shot) as COVID infection appears to not create enough immunity. After this the body has had enough “practice” identifying the COVID virus and is ready to “go it alone” against the real thing.

      Because they are using synthesized genetic strands without a virus(something not found in nature) they need to preserve them for long periods of time to make sure they don’t just “fade away”. So they need to keep the temperature at a point where biological processes “freeze up” and stay that way until the moment a person can be injected. Otherwise it would be an injection of a whole bunch of nothing if left in room temperatures.

    • The “injection of a whole lot of nothing” as Xander K. mentions, is likely going to be the issue in cases of improper storage. I can’t imagine every step in the supply chain from loading dock to injection site everywhere having 100% effective processes/people in place to ensure integrity of a product with such a ‘non-standard’ storage requirement. This could create situations of people thinking they’re protected when they’re not, and all that goes along with that. Haven’t read much on why 2 doses are required, but going by the articles on some clinical trial volunteer experience, where the first shot caused mild symptoms and symptoms after the 2nd shot were stronger, it appears the 1st shot is a pre-conditioning for administration of the more effective 2nd shot. So administration in 1 shot would do more harm than good for this formulation.

  • Wow. This makes me appreciate all the more the work of Moderna and Pfizer who managed to get their results, while the next several candidates all seem to be having issues. Oxford mis-dosed a whole portion of their study and found more efficacy, but in the correctly dosed, less so. In Australia, they’ve got false HIV positives. And now this, under dosing due to commercial reagents.

    • Underdosing due to commercial reagents or because they were trying to make (even) more profit? I can’t believe they are thinking of using an under-tested vaccine as a placebo! OMG what are you people thinking!!!

    • @steve Harding

      Conspiracy theories are decidedly unhelpful. Nothing is “under-tested”, and no one tried to make even more profit by underdosing. Non-adherence to study protocol is non-adherence to study protocol and is the the opposite of saving money. Clinical trials are expensive and having to repeat them is decidedly un-fun.

  • Is it just me or is anyone else really surprised by this? I’d have put my bottom dollar on Sanofi/GSK.

    • Sanofi Pasteur vaccines tried to use the insect-incubation technology they purchased from Protein Sciences corp to create a ‘Flublok for Covid’. The way flublok is made is an alternative to viral vaccines made in chicken eggs. Simple right? Thing is they appear to have used a cookie-cutter formulation approach to just simply use the flublok process of producing viral proteins. The amount of viral protein produced wasn’t enough to confer immunity to older adults (over 49). The mRNA approach used by BioNTech and Moderna is more novel in that it triggers expression of the spike protein of the covid-19 virus, not simply viral particles. More specific has shown to be more effective, so why be surprised that Sanofi’s version of the now historical In Ovo method didn’t pan out?

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