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Vaccines. From promising results to what can still go wrong

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Vaccines. From promising results to what can still go wrong

"It is still too early to say whether one strategy will work better than another," says Maria João Amorim, a researcher at the Gulbenkian Institute of Science, in Oeiras. "Some strategies have already been extensively tested and work for other cases (such as inactivated viruses) and there are other strategies that are absolutely innovative and for which we do not have large data (such as the use of genetic material from the virus)."

The great advantage of using fragments of the genetic material of the virus, as is being done by Moderna, is to reduce the amount of adjuvants (the components of the vaccine that help deliver the virus or parts of the virus to the immune system and that stimulate its answer), because it is these components that normally trigger adverse side effects. The disadvantage is that if viral DNA is used, it has to enter the nucleus of human cells and there is a risk that it fuses with human DNA. Moderna uses messenger RNA, which does not need to enter the nuclei and is already ready to transmit to the cell information on how to produce the viral protein. When this protein appears on the surface of cells, it is detected by the immune system. However, there is still no vaccine of this type on the market.

What research groups are looking for right now is that their vaccine can stimulate the production of neutralizing antibodies, those that bind to the virus and prevent it from entering cells. In fact, it's like we stick a little bit of plasticine to the virus key and he can't use it in the cell lock afterwards.

Use a virus with another's crown

Moderna announced that it was possible to detect this type of neutralizing antibodies, but the results and the way they were announced raised doubts. The Feng-Cai Zhu team, from the Center for Disease Prevention and Control in Jiangsu province (China), in turn, presented the results results in the renowned scientific journal The Lancet. The study that took place in Wuhan used a virus modified with SARS-CoV-2 crown proteins and got the volunteers' immune system to produce neutralizing antibodies and specific T cells (another important component of the immune response). The authors consider that the results allow to advance this approach to the next phase of clinical trials.

China says it is already testing five vaccines on people

This trial, like that of Moderna, served, however, to assess the safety of the vaccine. Of the 108 volunteers, 87 had side effects, weak or moderate, after vaccination – pain at the site of the bite, fever, tiredness, headache and muscle pain – without significant differences between the type of dose given, and which passed naturally on shortly.

The authors recognize the limitations of the work, such as the reduced number of volunteers, the short time that the participants were followed after vaccination (28 days) or the fact that none are over 60 years old, when the risk group is precisely above this age. The team hopes to have more responses as it progresses to phase 2 and 3 clinical trials.

The results in animal models

Feng-Cai Zhu's team also referred to the unpublished results of pre-clinical trials with ferrets, in which seven of the eight vaccinated ferrets had no signs of virus in the nostril harvest – against the unvaccinated group, in which seven in eight indicated the presence of viruses in the nostrils. The absence of detectable virus in the sample collected in the nostrils is a good indicator that the virus has been neutralized, that is, that after the infection, it was not able to replicate.

Another Chinese team, led by the biotech company Sinovac, showed that a vaccine based on inactivated SARS-CoV-2 led to the production of neutralizing antibodies by the immune system of rats, rats and monkeys, according to the results published in the journal Science. The team also concluded that, “although it is still too early to define the best animal model for the study of SARS-CoV-2 infections, rhesus monkeys that mimic Covid-19-like symptoms after SARS-CoV-2 infection they seem promising animal models for the study of the disease ”.

The rhesus monkeys were also used by a NIAID team to test the ChAdOx1 nCoV-19 vaccine developed by the Jenner Institute team at the University of Oxford (UK). This vaccine also uses a modified virus to which SARS-CoV-2 crown proteins have been added. Vaccinated monkeys produced neutralizing antibodies and did not develop pneumonia when exposed to the virus, pre-publication (not peer reviewed) in bioRxiv.

Infected monkeys gained antibodies against the virus 14 days after receiving the vaccine from the University of Oxford

But all the monkeys, vaccinated and unvaccinated, had traces of the genetic material of the virus in their nostrils – it was not possible to determine if they could still transmit the virus or if they had been exposed to a very large viral load (much greater than would happen under natural conditions). “If they only protect against lung disease, it is already an advantage”, says Observador Luís Delgado, professor of basic and clinical Immunology at the Faculty of Medicine of the University of Porto. “But this is not the type of vaccine that is sought for SARS-CoV-2, which is an extremely contagious virus. We want a vaccine that cuts the chain of infection. ”

Douglas Reed, an aerobiology expert at the Center for Vaccine Research at the University of Pittsburgh (Pennsylvania, United States), raises some doubts about the results in monkeys, because he says they only develop mild symptoms when infected with coronavirus. And to understand whether vaccines really prevent transmission, it would be preferable to test on ferrets and hamsters that are naturally susceptible and that seem capable of transmitting the virus, says to Nature.

Moderna also carried out laboratory tests, but with rats, and announced that it had managed to get the vaccine to prevent the virus from replicating in the lungs. The problem here, how indicates Nature, is that the SARS-CoV-2 virus (including the crown protein that many vaccines are using) had to be modified to be able to infect the mice, which can change the immune response in the mice and makes it difficult to extrapolate the mice. results for humans.

Humans have lived with coronaviruses for a long time, just think that some of them manage to cause the common colds. SARS and MERS are also coronaviruses, but these cause more worrying infections. Still, it was not possible to develop a safe and effective vaccine for any of these viruses, because the outbreaks were controlled before that happened. "Nobody finances things that don't seem very relevant anymore," says Marc Veldhoen. But the investigator believes the threat is now big enough not to be overlooked.

One of the problems with the development of SARS vaccines was the immune response that unleashed: vaccinated animals had more severe illnesses after being exposed to the virus than unvaccinated animals. The vaccine against the new coronavirus, although it is based on the experiences of the SARS vaccine, will have to take care of this aspect. None of the experiments with rhesus monkeys referred to here detected these negative effects.

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