Brazil Rejects the Gamaleya Vaccine | Hacker News Reader

Brazil Rejects the Gamaleya Vaccine

blogs.sciencemag.org

230 pointsClewza313115 comments

Virologist Dr. Angela Rasmussen about the ability of the vector virus to replicate

https://mobile.twitter.com/angie_rasmussen/status/1387397186...

In the linked Twitter thread, Dr Rasmussen says that a consequence of the Ad5 vector becoming replication competent is that the E1 gene might have replaced the spike protein, rendering the vaccine ineffective.

Are there any other consequences to the Ad5 vector virus being able to replicate? Is the virus harmful to humans in any way, or does it have the potential to become harmful?

Typically Ad5 causes upper respiratory tract infections which may manifest as a cold if you’re lucky or lead to pneumonia if you’re not, although things like conjunctivitis and gastroenteritis are not unheard of. Obviously we don’t know how applicable this knowledge is to the Sputnik Ad5.

From the article: "The Ad5 variety has infected a solid proportion of the entire human race [...]. It’s believed that if you already have antibodies and T-cells primed against the Ad5 vector itself (for example) that delivery of its payload will thus be impaired, leading to a less-effective vaccination."

A reminder that "U.S. officials pushed Brazil to reject Russia’s coronavirus vaccine" [0] for political reasons.

> Under a section titled “Combating malign influences in the Americas,” the HHS report states that countries including Russia “are working to increase their influence in the region to the detriment of US safety and security.” The global affairs office coordinated with other U.S. government agencies “to dissuade countries in the region from accepting aid from these ill-intentioned states,” it says.

The concerted effort to smear the Russian vaccine is clearly the Western version of the anti-vaccine misinformation Russia has been accused of spreading. Textbook projection.

[0] https://www.washingtonpost.com/world/2021/03/16/hhs-brazil-s...

Brazilian here, but just a regular guy, I didn't dug deep into this. Anvisa (our health regulatory agency) is well stablished before current president, supposedly independant and more often considered in opposition to current government. I find it unlikely that they are fabricating a rejection and more likely they are being cientific about it.

Same here. If what they say is true, that there was viral reproduction in the vacine, theres no way is gonna pass. They schedule a session in congress with Anvisa to defend their position, and decided to not show up to the meeting. The resistance in allowing European heath agencies entering and inspecting it's labs is also a bad sign.

I talked with a friend with ties in Anvisa. After all the bullshit the current president make they go through, with all the hydroxychloroquine thing, they kind of done a no interference pact over there among the staff, to not allow political pressure to dictate the result of their work. That say, nothing is immune to politics. But I don't think this was the case.

It's not only that, but the manufacturer refusal to present all kinds of evidence was very public and undeniable.

It is not that Anvisa is taking a political stance, but they operate under requirements of the government. The government is making it difficult for Anvisa to gather the data they need to make a decision.

How did the government interfere?

Here's a follow-up post on the behavior by the Sputnik V Twitter account https://blogs.sciencemag.org/pipeline/archives/2021/04/28/ru...

Greg Lowe is a very respected commentator on all things vaccines.

Derek Lowe.

This is not mutually exclusive with the findings of the Brazilian investigators. More than likely this will spur other investigations which should find the same thing if the Brazilian investigators were correct.

Brazil is using the Chinese vaccine. Don't think they would if those claims were true

Making sense in your head and fitting a narrative is not enough to make a claim correspond to reality.

The same organisation is putting pressure on Pfizer as well for lack of quality-control data: https://valor.globo.com/brasil/noticia/2021/04/26/impasse-co... (in Portuguese).

It looks like it shouldn't have been approved in the first place then.

it reports that they in fact had the data they needed for the Pfizer vaccine in February. Sounds to me like it was just a communication issue between Anvisa & the Ministry.

For me, this really calls into question the efficacy numbers published for the Gamaleya vaccine. e.g.: The Gamaleya National Research Center of Epidemiology and Microbiology and the Russian Direct Investment Fund (RDIF) have reported that the Sputnik V Covid-19 vaccine showed a 97.6% efficacy. [0]

[0]: https://www.pharmaceutical-technology.com/news/russia-sputni...

Lancet seems to be a respected journal and it confirms those numbers.

The vaccine described in the paper published in The Lancet was explicitly described as using an replication deficient Ad5 vector, while the vaccine received by Brazil seems to have been replication competent.

Considering Slovakia also said that Russia did not deliver a vaccine matching the characteristics of the one in The Lancet, I think those data are basically irrelevant now.

The vaccines delivered to Brazil also have a replication deficient Ad5 vector, Anvisa says that among the vast majority of replication deficient vectors some replication-able viruses were present.

There is pretty much no chance at all that this affects efficacy.

> Anvisa says that among the vast majority of replication deficient vectors some replication-able viruses were present.

Do you have the source for this claim? Linked Anvisa slides page 6 says "todos os lotes" (all lots) had replicating virus.

I agree this is about quality control and it is extremely unlikely to affect vaccine efficacy. (If anything, it would improve vaccine efficacy.)

I will try to find the source again, however I would read todos os lotes as saying that there are detectable replicant viruses.

Replicant viruses do not carry the spike protein, they don't contribute to antigen protection.

> Replicant viruses do not carry the spike protein, they don't contribute to antigen protection.

Are you sure? Do you mean that all of them must have had recombination that added the E1 gene and dropped the spike protein?

Indeed. So if a virus is able to replicate it must have a replication-competent E1 gene which normally encodes for the spike

> I agree this is about quality control and it is extremely unlikely to affect vaccine efficacy. (If anything, it would improve vaccine efficacy.)

I don’t think you can say this with much certainty, if the viruses either regained or never lost E1, it’s also possible that the same is true with E3 which modulates immune response.

Also, either of these genes could’ve replaced the Coronavirus spike protein.

The problem in Slovakia is that the delivered vaccines are in the form of a lyophilisate (pulver), one dose per vial. The vaccine described in Lancet was in liquid form, five doses per vial.

Lancet is not "respected" after their autism fraud scandal. Re-publishing Russian state-sponsored research is not "confirming those numbers" it's just low editorial standards.

The Lancet didn't perform those tests, they only published the numbers provided by researchers overseeing the trials. The first author of the source paper is Denis Logunov [0] who works at the Gamaleya Research Institute [1].

[0] https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

[1] https://g.co/kgs/u6wvJ8

Just like they do for every other vaccine. Every result was provided by researchers overseeing the trials for their own vaccines, nothing different here.

Scientific journals do not perform medical tests.

Just a reminder that the journals don't reproduce the research before publishing the article. They only check that somewhat intelligible, somewhat new, somewhat interesting. The more serious the journal, the more strict the checks.

So the numbers are not confirmed by the Lancet, they are just published in the Lancet. It's much better than reading numbers that are published in a blog, but it's not a 100% proof that they are correct.

Most scientific journals only do peer-review by sending articles to other scientists. These scientists, most of the time, only check for logical errors, and are not able to replicate the experiments.

it's important to make clear that what make the vacine being reject was not because of this number. The problem is that they remove the dna part of the virus that allow it to replicate once injected. But in all samples that they tested, in multiple batchs, they found replicant Adenovirus, that could make people who received the vacine sick.

That said, this is not a total rejection of the vacine. This is a rejection of the batches that where going to be imported. There are plan to produce this vacine in Brazil, and this batches could be approved in the future, if they did not find the same problems.

You cannot trust the Brazilian government to make this judgement. It is a policy of that government to delay the approval of vaccines as much as possible, as if there was no actual pandemic going on. Other governments around the world have analyzed the vaccine, including Argentina and Mexico, and they're using it without any problems.

article clearly states that other governments have raised similar concerns. Its not just brazil

in fact, article states brazil wasn't even the first

Argentinian government basically told it's own version of anvisa to approve the vaccine. That's it.

That's nonsense, most governments around the world are approving vaccines on an urgent basis. This is true for every vaccine. This doesn't mean that the government forcing any vaccine to be accepted.

Here it did. It didn't allow the agency in charge of that approve it.

If the vector is replicating, does that explain some piece of why Sputnik V is significantly more effective than the other adenovirus vector vaccines? (If that's even true, of course, since it may well not be!) Or is it simply a more effective preparation of a vaccine, due to things like the Ad5/Ad26 combination?

Has there been any controlled study on the efficacy of Sputnik V? I haven't heard of any.

You're asking if there has been any controlled study of Sputnik V, a vaccine which has been administered to millions?

Yes there has been. https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

> If the vector is replicating, does that explain some piece of why Sputnik V is significantly more effective than the other adenovirus vector vaccines?

The observed discrepancy between the delivered vaccine and the one described in the published clinical trial could, if not explain, hint at the reason the published clinical results are better than other vaccines in the same class.

Unlikely, because the part of the adenovirus they delete that allows it to replicate is what they replace with the portion that generates the spike protein antigen. So if some of the adenovirus is replicating it's inherently not doing what you want it to do to produce an immune response.

Not inherently. We don't know how it's replicating.

Furthermore, this isn't even an an/or situation: the actual virus in the vial of vaccine isn't going to be 100% uniform. You could have both virus material that can and can't replicate simultaneously. The extra immune response induced by the subset that can replicate might even make the immune response against the spike protein stronger, even if your theory is correct. Remember that vaccines usually have to use adjuvants to induce a stronger immune response than the active part itself does. An actual infection could do that quite effectively.

More importantly is it possible to infect others with the vaccine?

The respone from Gamaleya: https://sputnikvaccine.com/newsroom/pressreleases/sputnik-v-...

To me Gamaleya is turning a thecnical decision in a political one. Thanks to mistakes and possible crimes commit by the Brazilian goverment, when rejecting other vacines, they are now being pressured in accepting this vaccine no matter what. I don't think this is how a sanitary inspection agency should act, approving things based in pure pressure.

> Thanks to mistakes and possible crimes commit by the Brazilian goverment, when rejecting other vacines

Well, that's the first COVID-19 vaccine the Brazilian government has rejected.

Not really, Covaxin was also rejected about a month prior.

However I believe the original comment refers to the refusal of the Brazilian government to commit/invest in any of the vaccines while they were being developed, then stubbornly dismissing the importance of vaccination while promoting snake oil treatments.

Yes. The president of Brazil is now fighing a against a Comission in the brazilian senate that is revising all the work of lack of that the brazilian federal goverment put in the figth against Covid. This is now problably the moment of more political fragility he ever been,

Governors and mayors tired of waiting for the federal goverment that is still dennying the gravity of the situation, formed a group to import vacines by themselves. The problem is that there's no vacins avaliable in the market because there still a lot of nations that got first in the line, and production is still not enougth. The alternative that they got was coaxin that was rejected, and the russian vacine, that have thisconfidence problems that led to it being reject.

Bolsonaro actively campaigned against the vaccine that is responsible for about 98% of the doses administered to Brazilians because it was seen as sponsored by a political adversary.

Which Derek Lowe tears to shreds in a followup:

> These claims are bullshit. Posting them is a disgrace.

https://blogs.sciencemag.org/pipeline/archives/2021/04/28/ru...

For the record, I believe that's the very first time I've seen him use the word "bullshit", and I've been following him for over 10 years.

I wonder how much we are seeing general problems with adenovirus vector vaccines (e.g. blood clotting and this manufacturing issue) only because we've never rolled a vaccine out to a large population so quickly. Regulatory agencies are likely afraid to approve any at this point, which does not bode well for other vaccines using the same technology.

Intuitively speaking, using a viral vector has inherent risks that aren’t present with mRNA or protein subunit vaccines. To the extent that the latter technologies prove effective for vaccines against various viruses, I would think viral vectors should not be a preferred technology going forward for vaccine development.

Intuitively, the risks of viral vector vaccines are well known because they have been used for at least a decade while mRNA are being used in large scale for the first time only now.

Perhaps previously, but at this point hundreds of millions of people have been injected with mRNA vaccines and the safety profile and efficacy seem much better than any other vaccine technology.

But we haven't seen long term effects of mRNA vaccines.

I am not expecting a "children of men" distopy, and I'd rather have an mRNA vaccine than any other, but it is possible there might be some unexpected issues in the long run.

Weren’t the first viral vector vaccines (for Ebola virus) only recently approved?

As to track record, the first viral vector vaccines in widespread use (i.e. the COVID vaccines) will have killed hundreds (possibly even thousands) of people via blood clots. That’s a worthwhile trade off for a disease as deadly as COVID. But it would be less acceptable against less dangerous diseases, particularly if safer vaccine technologies are available.

The MMR vaccine contains "live" weakened virus. The kid sometimes get some small red points in the skin that disappear in a few days.

The oral polio vaccine "Sabin" has "live" virus. It's stronger than the injectable polio vaccine, but there is a small risk that the virus can escape and mutate and after a year or so cause polio to another person. So countries without polio cases, only use the injectable version "Salk" that does not contain "live" virus.

The first smallpox vaccine was just a similar virus for cows. The latest smallpox vaccine also used a "live" virus.

None of those are VVVs, though.

I am not a virologist, but blood clotting might be related to the specific payload rather than the platform. The original SARS-CoV2 has the same property. Could it be related to the spike protein?

This preprint suggests AZ vaccine blood clotting is due to EDTA, an ingredient specific to AZ vaccine and absent in other vaccines, and is related to neither platform nor payload.

https://www.researchsquare.com/article/rs-440461/v1

EDTA is an anti-coagulant, though. Blood collection vials are coated with it to prevent clots in blood samples.

The adenoviruses themselves are known to cause blood clotting for years and were questioned long ago as being a good vector.

These are the first widely deployed adenovirus vector vaccine.

There have been several rounds of trials of adenovirus vectors vaccines, but they never went forward to widespread use.

Viral vector vaccines are a less new concept than mRNA vaccines, so it might be easy to see one as new and the other as traditional, but they're both new.

My intuition, given the absolute (small) magnitude of blood clots, is that it’s not a huge issue.

Except that it is, because it has people spooked. Humans, myself included, are just terrible at gauging relative risk, and it doesn’t really matter that you are way more likely to die in your car driving to get the vaccine than from any vaccine complication. You are putting this in your arm, and people find it scary when even the tiniest issues crop up.

(I’ll snark a bit here: wonder how many people who are scared of vaccines smoke cigarettes…because, in terms of risk…hoo boy.)

It's not considering the disease it's protecting against and the currently likelihood of getting it, but if we were talking a flu shot or a vaccine for some much less common disease that math would change.

> My intuition, given the absolute (small) magnitude of blood clots, is that it’s not a huge issue.

Except there are two other vaccines with no risk of bloot clots. So if you can choose, why not choose the ones that aren't linked to that?

Ofc, that mostly goes for the US and EU who have secured supply.

The J&J vaccine, at least, is approved for single dose administration. That’s much easier for many people to handle then a 4 week return to someplace for a second round. If you risk getting fired for taking time to get vaccinated, only having to do so once is obviously better.

What ?!?

Where I am employers are legally obligated to give a day off for vaccination...

That's not true around the world, and even then, you'd need to lodge a complaint and get it resolved for it to do you any good. A lot of people don't have the financial security necessary to handle that kind of event.

Beyond that, there are people who are unlikely to come back for a second dose - homeless people, those with drug problems, etc. From a public health perspective, getting those people an effective vaccine is very important because they're generally at higher risk of getting infected and transmitting it to others, in addition to generally poorer health.

But the bigger news was that Anvisa, the Brazilian drug agency, said that every single lot of the Ad5 Gamaleya shot that they have data on appears to still have replication-competent adenovirus in it.

Sounds like a manufacturing quality-control problem. This is why you need so much sampling and analysis in drug production. It's probably fixable, but denial will not help.

Covid19 has been extremely politicized in Brazil. President's supporters were mostly against vaccine until coronvac (sinovac vaccines) was approved by anvisa, Brazil's equivalent to FDA.

In Brazil this pandemic took ridiculous proportions. In the beginning, it was said that it wouldn't kill even 800 people[0]. It was said that it would be no more than a little flu and that children should not skip schools[1]. After thousands deaths, the president said, when asked about it, "So what?"[2].

Parallel to that, special secretary of culture, (which was once ministry of culture), was ousted[3]. She was replacing the previous secretary who (SERIOUSLY) emulated Goebbels on an official announcement[4]. On the education side, a "twitter-boy" with spelling difficulties[5] replaced the previous minister who was very weak technically[6]. It was then replaced by a liar[7] and then by an homophobic[8].

Some states then started restrictive measures to control the spread of the virus. The president was against it, the supreme court had to intervene to guarantee that states could apply restrictive measures[9]. A false narrative started trying to blame problems during the pandemic on governors because the president "couldn't act". A false dichotomy also spread by supporters saying that restrictive measures hurt economy and that it could kill more people than the pandemic. It actually is the opposite, but it has grown among his supporters.

Then came choloquine, hidroxicloroquine, ivermectin, and nitazoxanide, not exactly in this order. The Chloroquine 'venture' was the most interesting. The president pressured the health minister to encourage it. As he refused, he was ousted[10]. The same pressure was tried on the next minister. He was ousted too[11].

Things got worse and his supporters began anti-democratic demonstrations asking for a pro-president coup[12]. Supreme court was attacked and people were arrested[13].

While the president discouraged the use of masks and social distancing, the number of daily deaths stayed on an elevated plateau[14]. Debauchery of sick and dead became common[15].

By the end of the second half of 2020, some vaccines were offered but refused[16][17]. The minister asked "why such a hurry?"[18] and the president said "The hurry is not justified"[19].

Things improved a little by the end of the year, people relaxed and met their relatives on year end's festivities. This had consequences and 2021 arrived. New variants surged and number of deaths started to rise again. In Manaus, hospitals run out of O2 and people suffocated to death[20]. Variants continued spreading and another health minister was replaced. Vaccines were approved and people began to be vaccinated.

By the end of April with around 14% of the population having at least one vaccine dose, numbers of daily deaths began to fall.

Some facts were not listed on the correct order, but today is April 28 and, according to worldometers.info, we're now at position 14 and soon there will be more deaths per million than in the UK. Brazil has the lowest median age population among nations with the most deaths.

No other country handled the pandemic worse than brazil.

[0] https://www.dw.com/en/opinion-bolsonaro-lets-100000-die-of-c...

[1] https://edition.cnn.com/2020/05/23/americas/brazil-coronavir...

[2] https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

[3] https://www1.folha.uol.com.br/internacional/en/culture/2020/...

[4] https://www.theguardian.com/world/2020/jan/17/brazil-culture...

[5] https://www.france24.com/en/20200110-brazil-s-education-mini...

[6] https://brazilian.report/power/2019/03/28/brazil-disastrous-...

[7] https://www.theguardian.com/world/2020/jul/01/brazil-educati...

[8] https://www.telesurenglish.net/news/brazil-education-ministe...

[9] https://www.aljazeera.com/news/2021/3/20/bolsonaro-asks-supr...

[10] https://brazilian.report/liveblog/coronavirus/2020/05/21/for...

[11] https://www.hindustantimes.com/world-news/bolsonaro-s-love-f...

[12] https://www.dw.com/en/brazilian-president-bolsonaro-sides-wi...

[13] https://brazilian.report/liveblog/coronavirus/2020/06/14/bra...

[14] https://www.theguardian.com/world/2020/jun/23/brazilian-judg...

[15] https://www.theguardian.com/world/2020/jul/08/bolsonaro-mask...

[16] https://theconversation.com/brazils-president-rejects-covid-...

[17] https://apnews.com/article/virus-outbreak-brazil-state-gover...

[18] https://www.nytimes.com/article/brazil-coronavirus-cases.htm...

[19] https://www.reuters.com/article/uk-health-coronavirus-brazil...

[20] https://www.caritas.org/2021/02/oxygenformanaus/

> No other country handled the pandemic worse than brazil.

Yup, even Bloomberg agrees: Brazil is at the very bottom of the resilience rankings.

https://www.bloomberg.com/graphics/covid-resilience-ranking/

You make a good case, but you do have to admit that Narendra Modi is also a solid contender for shittiest handling of COVID. Just letting the Kumbh Mela go ahead this year earns him a spot near the top.

Live by ideology, die by ideology.

I am not trying to defend the Indian PM, whom I barely know by name, but it is not as if the West does not have similar weaknesses. Mass BLM rallies were allowed to go forward because the political price for banning them and enforcing the ban through use of force would have been too high. Even though it was already known that going to rallies is a risky behavior.

Fortunately for the U.S. at that moment, no extra infectious variant was in circulation. AFAIK India has a nasty variant that makes things worse.

India is catching up

That is not mutually exclusive to investigators finding problems with Sputnik V.

And...?

It’s being said they didn’t actually test it.

"Being said"... Let me guess, Sputnik News?

https://www.ndtv.com/world-news/scientists-back-brazil-over-...

> According to a slideshow uploaded online, scientists at Anvisa, Brazil's regulator, said they *tested* samples of the booster shot and found it was "replication competent" -- meaning that once inside the body, the adenovirus can continue to multiply.

No.

https://www.google.ie/amp/s/super.abril.com.br/blog/bruno-ga...

“Nível de RCAs, principal argumento usado para vetar o imunizante russo, não foi medido pela agência - que afirma ter se baseado em documento do próprio Instituto Gamaleya”

I would like to add information that I believe is very relevant.

During the pandemic, the congress approved a law (Article 16, Law No. 14.124/2021)[1] that defines a limit period of 30 days for Anvisa to approve or disapprove the vaccine. If, after 30 days, Anvisa does not issue its final recommendation, the vaccine is automatically approved. I think this law is absurdly stupid, but let's get back to the facts.

Days before denying Sputinik's authorization to use, Anvisa asked the Federal Supreme Court (STF) to suspend the 30-day period alleging that the data received were incomplete and information was missing.

A supreme court judge denied, on March 26th, the suspension of the deadline saying that this possibility was not manifested in the law. And he added that Anvisa's decision must be technically based, "not admitting the mere allegation of insufficient documentation or the simple allusion to potential risks". And if Anvisa does not decide on import and distribution authorization requests within 30 days, the interested parts are automatically authorized to import and distribute Sputnik V [2].

One day after the judge denied the suspension of the term and one day before the deadline, Anvisa denied the request.

[1] https://www.in.gov.br/en/web/dou/-/lei-n-14.124-de-10-de-mar... [pt]

[2] https://agenciabrasil.ebc.com.br/saude/noticia/2021-04/lewan... [pt]

The automatic approval law is incredibly stupid. Your timeout mode shouldn’t be to automatically approve medicines when the regulator takes over a month to issue a decision.

Thanks for the context, this is probably a large part of the decision. Not enough time for due diligence, and the only option to prevent automatic release of a potentially problematic medicine is outright rejection.

I'm a complete layman but reading about the replication prevention I wonder:

Could it be that they left E1 intact deliberately? I suppose (naively) that a virus that replicates should cause a stronger immune system response and therefore increase efficacy. Being an adenovirus the worst thing that could happen is that you get a common cold.

Common cold once vs potential death is not the worst trade-off imaginable, if you ask me.

Gamaleya themselves says they removed E1. There is no reason to doubt it.

Thanks, that makes sense.

This is addressed in the article:

Now, there have been debates over the years about whether you’d get a more effective vaccine that way, with a “replication-competent” adenovirus, but generally it’s believed that you can do fine with the “replication-incompetent” ones, which let you *not* give your patients a new viral infection at the same time.

Thanks, that takes away the premise of my question.

Also, would this be transmissible? Could vaccinated person A infect unvaccinated person B, leading to community transmission of immunity?

I'm not an expert in this field, but it sounds logical at least, and provides a motive for the discrepancy.

I thought this NY times op piece on Russian and Chinese vaccines was interesting:

https://www.nytimes.com/2021/02/05/opinion/covid-vaccines-ch...

It’s Time to Trust China’s and Russia’s Vaccines

Basically non-western medical companies such as the Russian and Chinese vaccines companies have a much higher bar to reach in order to get their products approved.

Quality control issues and incomplete documentation are serious problems, but also fixable. Right now the world (maybe not us in the west) need Russian and Chinese vaccines as what the west can offer is not enough to go around.

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