Vaccines, successful centenary tools
The effect of vaccines in the prevention of infectious diseases has been very important and COVID-19 is the last example of it.
Vaccination is one of the most successful public healthcare interventions in history. Since Edward Jenner’s work with smallpox in 1796, this scientific advance has transformed the relationship of human beings with potentially severe diseases such as measles and poliomyelitis. The relevance of this therapeutic solution has been proved again with COVID-19, where the rapid development of, to date, eight different vaccines can be the beginning of the end of the pandemic and can transform the future of this preventive tool.
Vaccines use the ability of the immune adaptive system to identify and remember the antigens of pathogens. That is, proteins and other fragments of viruses and bacteria that attack the body cells. The goal of this therapeutic tool is to train this system artificially so that it produces a response against future infections, but without suffering the consequences of the disease. “Adverse effects of a vaccine cannot be compared to the effects of the infection, as different studies have shown the risk of complications of the disease or the wild virus is infinitely higher”, notes Anna Vilella, medical adjunct lecturer at the Faculty of Medicine and Health Sciences and senior consultant at the Department of Preventive Medicine and Epidemiology of Hospital Clínic.
An idea that resulted from smallpox
The father figure of vaccines was the English doctor Edward Jenner, who, in 1796, realized that milkmaids who were infected by cowpox, not severe in humans, did not suffer the consequences of smallpox, a disease that was killing three out of ten infected people and which was an important cause of blindness. Later, he showed that the pus taken from pustules caused by cowpox could be used to immunize humans against the smallpox infection and this is how a revolution in public health began.
A hundred years later, French scientist Louis Pasteur, one of the promoters of the theory that stated that diseases were caused by microorganisms, developed the vaccine against rabies with weakened viruses unable to pass the disease on. This advance was the start of a fertile period of creating new vaccines ─a term created by Pasteur, to pay tribute to Jenner’s work─, so that by mid-20th century, there were solutions with weakened or inactivated pathogens against severe diseases such as diphtheria, whooping cough, tetanus, cholera and typhus.
However, the key moment for vaccines as a tool in public healthcare was the coordination of comprehensive vaccination programs after the fifties, with a notable impact on children’s health. The World Health Organization (WHO) estimates that between two and three million lives are saved every year thanks to these initiatives. “Vaccines are the best preventive tool, they helped us to reduce the impact of infectious diseases, which were the first cause of death for children under five years old”, notes Anna Vilella. These interventions enabled WHO to declare the elimination of smallpox in 1980, two centuries after the first vaccination, conceived by Jenner.
From weakened viruses to the messenger RNA
The research to obtain the right and safe molecules to design vaccines has evolved since those first discoveries. From Pasteur’s weakened viruses, researchers started to use viruses, or toxins in the case of diseases caused by bacteria, inactivated using heat or chemical products. Then, they would also use fragments of the pathogen, which they can get by isolating this antigen or using genetic engineering, such as in the vaccine against hepatitis B. “We need a vaccine that gives protection and that is as safe as possible. This is why we are looking for pure antigens so that they stimulate the immune reaction, but without causing adverse effects. The problem is that sometimes the immune system cannot react towards this pure antigen and we need to use more doses or to use adjuvants, chemical products or structures that work for the antigen to boost the innate response”, says Anna Vilella.
In this race to introduce the strictly necessary elements to cause the reaction of the immune system, the new approved vaccines against SARS-Cov-2 by the European Medicines Agency (EMA) went one step further: these transport directly the genetic instructions so that the cells develop the coronavirus antigens, specifically the S protein (spike or spicula) and therefore train the organism against this pathogen. “The Oxford/AstraZeneca and J&J/Janssen vaccines introduce these instructions via a DNA molecule stored in a viral vector, an adenovirus that cannot be replicated, it cannot cause diseases in humans, and it had been used in other vaccines such as the vaccine against the Ebola virus. Then, the Pfizer-BioNTech and Moderna vaccines use a messenger RNA protected by lipid nanoparticles, an innovative technology, although it has been worked on for more than 20 years”, notes Josep Maria Suñé Negre, professor of Pharmacy and Pharmaceutical Technology at the UB and director of the research group Service of Development of Medicines (SDM) at the Faculty of Pharmacy and Food Sciences.
COVID-19, a vaccine in record time
The process to develop a vaccine, and any drug, has to go through “a previous wide experimentation under a strict regulation before reaching the market”, states Josep Maria Suñé. The first steps, the preclinical stage, consist of experiments in the laboratory (in vitro) and on animals (in vivo). Once this phase is successfully over, they start tests with volunteers: the Phase I, with just a few healthy people, is to find the pharmacokinetic of the drug and to see whether it is safe. In the Phase II, the experiment analyses whether the drug is efficient and researchers study the most suitable dose. Last, in Phase III, they assess the efficiency and safety of the drug with a great amount of people. In this context, the creation of vaccines against COVID-19 has been stunning: on January 10, 2020, Chinese scientists shared online the genetic sequencing of SARS-COV-2. Forty-two years later, they had a vaccine ready to conduct clinical trials in humans and by December 11 they had the emergency approval in the United States, and then in the European Union, of the first vaccine against COVID-19, Pfizer-BioNTech. That is, in less than a year since the identification of the virus, a historical milestone, specially if compared to the chronology of the first vaccine against influenza, which got approved in 1945, fifteen years after the identification of the virus.
“In order to generate a new vaccine or medicine, if you have to find the active principle and conduct all the phases in the preclinic and clinical trials, it can take more than ten years to reach the market. With COVID-19, the virus was immediately identified, and with the experience of previous vaccines, international scientists studied the features and weaknesses of the new coronavirus to develop the vaccine”, stresses Josep Maria Suñé.
According to the researcher, this process has been marked by the “urgency and collaboration between scientists, public administrations, governments and pharmaceutical businesses” that brought human resources, materials and the economy to do achieve it. “An example of it are the regulating agencies that have to approve every step in the development of any drug and which usually regulate healthcare, physiotherapeutic and cosmetic products. They put together all efforts and resources to assess these vaccines, so they have accelerated the legal and bureaucratic side of it”, the expert says.
Also, given the situation of the pandemic, the assessment of the safety and efficiency of the candidates has been accelerated as well. “It would look like a less secure process, but it has been as rigorous as always and has passed all the phases in the clinical trials. Having so many cases has helped us. First, because you find volunteers to take part in clinical studies and then, because it is easier for these volunteers to be in contact with the infection and to test whether the vaccine works or not. If, for instance we wanted to assess the efficiency of a vaccine against measles it would be difficult because there are almost no cases”, notes Lorna Leal, expert and researcher at the Department of Infectious Diseases in Hospital Clínic and adjunct lecturer at the Faculty of Medicine and Health Sciences, who is member of a consortium to develop a new vaccine against COVID-19.
A new candidate with a promising technology
This project is developing a mRNA-based vaccine, the study of which is expected to start by early 2022. It is led by the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) ─Hospital Clínic, and counts on the participation of the UB, the Institute for Research in Biomedicine, Pompeu Fabra Institute, the CSIC National Centre for Biotechnology, the University of Santiago de Compostela, the Free University of Brussels and the animal health business Hipra, “To date, the approved vaccines with this technology provide the mRNA with the complete protein of the virus (protein S) to be identified by the immune system. In our case, using computational systems, we select the fragments of the protein that generate the best responses regarding antibodies and cell response, in order to get a specific immune response and avoid adverse effects”, describes Lorna Leal.
This project is based on the more than ten years of work of the team in IDIBAPS-Hospital Clínic using mRNA technology to find a therapeutic vaccine able to improve the immune response of the people who have HIV. “With SARS-CoV-2, we know we have to target antibodies against the protein S, but for HIV we do not know for sure against which proteins or fragments of the virus we should improve the immune system response, and it is a virus that can mutate infinite times more than coronavirus”, says the researcher.
For Anna Vilella, this mRNA technology can bring “the future of the vaccines, because it is a versatile technology, which can rapidly adapt in case of an emerging pathogen”. In this sense, Lorna Leal stresses that the obtained experience during the pandemic in projects and consortiums like hers will be very important. “Perhaps our vaccine fins it hard to find a place in the immunization against COVID-19, but the gained experience regarding scientific knowledge, technology development and the experience in manufacturing, thanks to the collaboration of academic entities and the business in which we take part in the consortium, will involve learning to get more resources to face a future pandemic in a better way”, concludes the expert.