Lower expectations: “We do not know if the vaccine will be successful and when it will arrive”

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This week saw another milestone in the Corona vaccine race, when the modern company and the development of Pfizer-Biontech entered the giant trials phase with 30,000 volunteers. At the same time, large trials are already underway by two other companies – AstraZeneca, which has developed a vaccine from Oxford University and is conducting an experiment on ten thousand volunteers, and the Chinese company Sinovac.

Expectations are high in the public and in the scientific community. Great joy was recorded after it became clear that all these vaccines raise the levels of antibodies to the corona virus in the blood. Although the question arose for a moment about the amount of “neutralizing antibodies”, which are really significant, but then it turned out that they too were discovered in the four leading vaccines.

However, Dr. Ami Neuberger, a senior physician in the Infectious Diseases Unit at Rambam Hospital, is still unconvinced. “Every honest person facing the situation must honestly say that he does not know if the vaccine will work, what the chances of success are and when it may come,” he says in an interview with “Globes”. “Despite the joy of vaccines entering giant trials, in terms of proving their effectiveness, they are still considered products at an early stage. We do not know much about them. Historically, the chance of a vaccine coming from Phase I trials in humans for approval is less than 10%.”

Not all diseases can be vaccinated

What exactly are “neutralizing antibodies,” and does their existence significantly reduce the risk of the vaccine becoming worthless?
“Let’s start with the fact that if we have antibodies, it’s good. It’s certainly better than a situation where they were not. This means that the immune system has seen the vaccine and reacted to it as the recovering patient responds to the disease.

“Neutralizing antibodies are antibodies that we think will work specifically against the virus’ linking sites to cells and neutralize its action. Vaccines usually work through neutralizing antibodies, so that’s what we’d expect to see at this stage of the experiment. It certainly raises the likelihood of success. But some diseases are already trying. “Years without success in producing a vaccine for them, even though they created substances that caused a temporary increase in neutralizing antibodies. This can happen for several reasons – the pathogen (virus in case of flu, or parasite in case of malaria) changes or the antibodies do not last long enough.”

Does it depend on the vaccine or the nature of the disease?
“It can be said that it depends more on the disease. The corona virus, meanwhile, seems relatively stable, compared to the AIDS virus, for example, which is constantly changing and therefore it is very difficult to produce a vaccine. But it has been found that corona viruses produce neutralizing antibodies that do not last long. The Sars-CoV-2 virus, our corona virus, has been detected in several cases where the antibodies seemed to decrease after a few months, however, it is not known to this day for sure about someone being infected twice.

“I also can not say unequivocally that it is not possible to create a vaccine that will provide long-term protection for a disease whose natural antibodies do not survive over time; I am just saying that there is a correlation between things. In measles, which naturally produces high amounts of antibodies over time, the vaccine “Very effective and prevents the disease almost 100%. In the flu, the vaccine is much less effective, and the partial protection is also relatively short.”

I thought that under the influence of the vaccine it is effective for life for a certain strain, and people still get sick again and again because the vaccine is not effective for other strains.
“That’s true, too, but the flu vaccine for a particular strain is also imperfect. In some years, the flu vaccine for a particular strain has protected only 60% of those exposed to it. The 2009 swine flu, for example, when it returns to a particular area, can be transmitted. “People who were vaccinated and did not get sick in the first round, or those who got sick and recovered.”

That is, even a vaccine against all strains of influenza will not necessarily become a perennial vaccine.
“True. We have known the effect for many, many years and still have not been able to produce the ultimate vaccine for it.”

So basically either we are lucky and the disease is suitable for the vaccine, and there is a chance that many vaccines will succeed, or the disease is less suitable for the vaccine, and then the challenge will be greater.
“It is very important that we say over and over again that our knowledge about corona is limited and these statements are mostly based on what little is known about this disease to date and what is known about other diseases, but in general it is true, very much depends on pre-existing disease and immune systems.

“The immune system is made up of many types of cells. If one of the vaccines succeeds it raises the likelihood that others will succeed, but it is completely unsafe.”

The ignorance — that the vaccine

Why everyone is afraid of dengue fever

Astrazenka and the University of Oxford reported that in addition to antibodies in general and neutralizing antibodies in particular, they also saw an increase in T cells in the immune system in their experiments, which is probably good. Neuberger explains: “This means the immune system responds to the vaccine in several ways. “You respond to the virus and if the response is specific. If the response is not specific, it increases the risk of side effects resulting from an overreaction of the immune system.”

According to Neuberger, the story that scares everyone is that of dengue fever, that if you get it twice, the second time the ward is more deadly, because the immune system is fighting too hard.

“There was one vaccine for dengue, which of course is no longer given, which actually turned the first time into a second, and increased the number of people who had severe side effects. We do not think such a phenomenon will return in Corona, because we have not seen a second illness at all and a particularly severe second illness in particular. But this is an example of the kind of things that can happen if the immune system is stimulated inaccurately enough, the kind of things that need to be taken care of. ”

According to Neuberger, the side effects reported so far in vaccine trials are reasonable and expected, such as fever, weakness and feeling sick, “which is something that is almost unlikely to be reported when you are injected with an experimental product, even with too much stress and attention to the body,” he says. Other side effects below. “If there is a side effect that affects 1 in 100 people, and so far only 50 people have tried the vaccine, there is a chance that we will discover it in the extensive trials, which are conducted in tens of thousands of people.”

If it were a more deadly disease than the corona, people might agree to take some risk, says Neuberger, but “Corona is a disease from which mostly adults die, and consistently in the vast majority of vaccines, their effectiveness decreases with age. So we must produce a vaccine to use. It also includes those who are not in a risk group. To convince young people to get vaccinated ‘for adults’, a very safe vaccine is needed. If the vaccine is 95% effective among young people, but only 30% in adults, it will still change the course of the epidemic completely. Of people at risk. ”

Do you see a willingness among the public today to get vaccinated?
“It all depends on the public’s trust in the process, and I believe it will be influenced by the experts’ trust. At the moment, it seems that the leading vaccines are expected to withstand large and comprehensive trials, which will allay any concerns that experts have.”

What percentage of the population needs to be vaccinated so we can take over the corona and get back into our lives?
“Depending on the effectiveness of the vaccine. If it is as effective as the measles vaccine, 80% -90% is enough to make a difference. If it is a less effective vaccine, like the flu vaccine, it is still very worthwhile to get vaccinated, but it will not get us back to normal.

“In this regard, the flu vaccine is very important this year, both because you do not want to come to a hospital with flu symptoms, and also because saving a few dozen respirators can make the difference between a functioning health system and its collapse.”

The battle for vaccine doses is still ahead of us

One of the questions about the vaccine development protocol was whether it would involve intentional infection of the volunteers in Corona (Challenge Trial), or whether they would vaccinate them and send them “to the big world”. How do you think it should have been done?
“So far no company has stated that it intends to conduct a challenge experiment, which involves intentional infection, although I personally think it is completely ethical. If it is real volunteers, not out of economic hardship or political pressure, a person has the right to say he wants to get sick. Save other people from death, and ‘on the road’ also save the world economy. People also go to reality for all sorts of different and weird reasons, and it’s allowed. I also think it would not be harder to get volunteers for such an experiment, because it can prove the effectiveness of the vaccine. Even in a smaller sample.

“When I heard the companies say the experiment would be over by October, I thought it could not happen without a challenge experiment, but in the meantime they seem to be going out for an experiment where the contagion is in the real world, and against that background, the stated schedules seem a little too optimistic to me.”

Along with the questions of efficiency and safety, another trap awaits the vaccines on the way – the question of production and transportation. “If you can’t easily get a vaccine without it being damaged, that’s a problem,” says Neuberger. “We have seen that GSK has joined the mission by collaborating with several companies, including the Chinese company Clover and the Canadian company Medicago, which has developed a plant cell-based vaccine. Both collaborations have already begun in human trials. GSK is developing an adjuvant that strengthens the vaccine and More dishes based on the same amount of active ingredient. ”

GSK is currently preparing for the production of one billion adjuvant dishes in the next 12 months.

“Once manufacturing issues are resolved, so will the political and economic issues: who gets the vaccine first? Every country cares about its citizens. The World Health Organization (WHO) has organized an initiative for fair distribution of vaccines. The U.S. has begun a process of separation from the WHO, and Donald Trump has already said “He wants to make the U.S. a priority. I’m sure if he can, he’s leave as many of the dishes as possible within U.S. borders.”

Neuberger, who has worked with the World Health Organization in Africa (see box), says he is a bureaucratic body that needs to be improved, but this is definitely not the time to dismantle it. We need it, among other things, to ensure that vaccines developed in China undergo comprehensive international trials. “Their results. We will have to see if the World Health Organization really takes care of that.”

Changes in treatment: “More will learn how leaders promoted a product even though doctors said it was not proven”

Between the first and second waves, there were changes in the way patients were treated, and first and foremost the number of souls decreased. “Less patients are now being treated because it is clear that some of the young people who are in respiratory distress are able to overcome the infection on their own even without the soul,” says Dr. Neuberger.

How close are we to a state of insufficiency in hospitals?
“In a hospital like ours we can reach 150-200 respirators, and then we will have to disable the rest of the hospital’s activities and that too has an end. I’m not in a panic, but I’m not complacent. We have seen how in Italy and the US they have fallen sharply.”

What other changes have you made to the treatment protocol?
“In the first wave, they also gave drugs that did not work in retrospect, such as hydroxychloroquine (HCQ) and an antiviral drug used to treat AIDS. They both had logic in the lab, but in real life it just did not work. He is less likely to prescribe an experimental drug.When there are no alternatives, they try everything.Everyone would do it, of course with the approval of the patient and his family, as much as possible.

“The HCQ will be listed as a chapter in the history of medicine. Its use stemmed from a hope that was fueled in several studies. They will also learn how Donald Trump, Emanuel Macron and Jair Bolsonaro promoted the product even though doctors said it was not proven, and later proved unhelpful.”

Did you also treat with antibodies of recoverers?
“Yes. It’s a treatment that makes sense, and so far it has no clear supporting evidence. It’s not clear how much antibody can be made from the blood of recoverers, and it’s also expensive and cumbersome. Producing antibodies within animal cells is more cost effective, but still harder than vaccinating. I do not expect That is where salvation will come from. ”

Do you also give some mental health care to a person who is hospitalized for a long time, without visitors, and sometimes without the ability to communicate on the phone?
“Dealing with a life-threatening situation is an end in itself for every person, and in this case the loneliness and uncertainty do aggravate the situation. We tried to involve social facts in the care of these patients in real time, but it is very difficult because of the need for protection and the situation.” During the recovery. ”

Africa’s anger: “I saw what a world without vaccines looks like”

Dr. Neuberger, who dealt with hospital preparedness in Africa during the Ebola epidemic, and also encountered other “forgotten” infectious diseases, warns of uncontrollable rage on the continent around the supply of vaccines.

“I saw what the world looks like without vaccines,” he says. “I have seen tetanus and measles and rabies, in children and adults. Anyone who wants to go back to nature must understand how cruel nature can be. Without bad intent, but terrible. With this memory it is very easy for me to justify getting vaccinated. I have seen children with rabies in Africa not vaccinated after being bitten. “Apart from trying to prevent them from suffering, nothing could be done. We and the parents just waited for them to die and hoped that they would suffer as little as possible.”

Is there an awareness that other countries have a vaccine for these diseases?
“In Africa? Sure. They know, and they’re angry. There are all sorts of horrible arguments like ‘they have a lot of kids and the value of human life in them is less.’ I heard these things, and not just about Africans. It’s just not true. Kids are just as important to them as they are. That they are important to us, and the pain of loss looks just like ours, even if it is more predictable.If the leaders of the Western world do not make the right decisions, it is a scenario that will repeat itself with the corona, and the rage will be difficult to control.

“Even within the United States, it was clear that there was no solidarity between the countries. New York collapsed, and other states did not come to its aid. “Such scenarios show that” countries in the United States are farther apart than we thought, and so are EU countries. Epidemics have always taken the evil out of humans, and this division is dangerous at the time of an epidemic. ”

Dr. Ami Neuberger

50 years old ● Specialist in internal medicine and infectious diseases at Rambam Hospital ● Worked in several Third World countries, including Equatorial Guinea and Haiti ● In 2014 he was on a mission from the Ministry of Foreign Affairs in Ivory Coast and guided local staff during the Ebola epidemic ● Additional positions: Rambam Traveler Clinic And consultant to start-up companies

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