We are seeing many countries accelerating Covid-19 vaccine development, a race that has become increasingly fierce.
We are seeing many countries accelerating Covid-19 vaccine development, a race that has become increasingly fierce.
Many comments, criticisms and praises have been made regarding this endeavor. Social media is also full of knowledgeable opinions. However, many people are also giving praise or criticism without any deep insight on this issue. Let us use a cool head in an attempt to understand the “vaccine race” to control the disease, which is now infecting almost 300,000 people every day.
Russian President Vladimir Putin recently announced on 11 Aug. that his country had become the first to successfully develop a vaccine. This vaccine will soon be used for mass immunization in October. Putin claims that the vaccine is safe, and that his own daughter volunteered in the clinical trial.
The vaccine is named Sputnik V, after the Russian satellite Sputnik I, which became the Earth’s first artificial satellite in 1957, beating the US in the space race. Russia has claimed that 20 countries have ordered more than 1 billion doses of the Sputnik V vaccine. Russia also offered the vaccine to the US, but its offer was rejected. However, some immunologists have criticized Russia for being too hasty in using the vaccine on a mass scale, fearing that it is neither safe nor effective.
Most recently, in conjunction with the Day of Proclamation of the Republic of Indonesia on 17 Aug., China patented a recombinant adenovirus vaccine named Ad5-nCov. The vaccine was developed by CanSino Biologics with a team from the Chinese military. Earlier, the Wuhan Institute of Biological Products developed a candidate vaccine from inactivated SARS CoV-2, which has reportedly become a mainstay of the World Health Organization (WHO).
Sinovac Biotech, another Chinese vaccine manufacurer, has gone even further: 2,400 doses of the Sinovac candidate vaccine have entered Indonesia. State-owned pharmaceuticals Bio Farma and the Padjadjaran University medical school held a clinical trial involving 1,620 volunteers that was observed by President Jokowi (11/8). The Food and Drug Monitoring Agency (BPOM), which licenses and supervises clinical trials, projected that the vaccine would be ready for mass distribution by February 2021. Sinovac was chosen as a partner because the manner and method it used to develop the vaccine was the same as Bio Farma’s, that is, the use of the inactive or attenuated virus.
However, this cooperation has raised raucous pros and cons among netizens on social media. The comments include why the Indonesian people have been made guinea pigs for a vaccine developed in China, which appears to be in a hurry to reach the production stage. Why not wait for a vaccine made in our country? Why is the nation only putting itself forth as a market for foreign vaccines? And other similar criticisms.
In the post-truth era, when social media is extremely influential in changing public opinion, the overwhelming criticism against foreign-made vaccines does not derive from expert analysis, but comes more of negative sentiment and views, whether in support or objection.
Please remember that vaccines are medical products based on in-depth, precise research. Touting their pros and cons without adequate understanding of the scientific process will only confuse people more. The academic perspective is necessary so that people do not just get caught up in emotive pros and cons.
Complex process of vaccine research and development
Vaccines are antigenic substances that are used to generate an immune response against diseases caused by viral infections. So, a vaccine is a weapon against viral infections. Using empirical processes, vaccine research takes a very long time; it cannot be developed impromptu.
Let us look at the history of successful vaccine development. The research needed to develop the varicella (chickenpox) vaccine and the FluMist (nasal spray flu vaccine) each took 28 years. The vaccines for the human papillomavirus (HPV; the virus that causes warts) and rotavirus (causes diarrheal disease in infants and toddlers) took 15 years to develop. The pediatric combination vaccine (for children) took 11 years to develop.
Vaccine development takes more than 10 years on average just for the research. Many variables require careful testing, but the main thing is the safety and effectiveness of the vaccine. The vaccine must be effective at generating an immune response against the target disease and it must not harm the patient, either in the short or the long term.
A vaccine could be effective at warding off infection with the “X” virus that appears to be safe for human use. However, it could be that it causes the emergence of dangerous side effects after a few years, such as ADE (antibody-dependent enhancement). This occurred in the development of vaccines for the dengue, Zika, and other viruses, which did not prevent disease and instead exacerbated infection. This kind of vaccine is effective, but unsafe.
The effectiveness or efficacy of a vaccine against the target virus is immediately evident, but proving the safeness of a vaccine can take much longer. Candidate vaccines require lengthy trials to prove their safe use in humans. These pilot stages are inflexible, highly standardized, and highly regulated for the purposes of maximum safety and efficacy. This is a brief overview of the long duration required for vaccine research; it cannot be done overnight.
As of 10 Aug., 165 vaccines were in the research stage and 30 candidate vaccines were in the human trial stage. To be more specific, 135 vaccine prototypes were in preclinical studies, 19 candidate vaccines were in the phase I clinical trial, 11 candidate vaccines in the phase II clinical trial, 8 candidate vaccines were in the phase III clinical trial, and just one vaccine (CanSino Biologics, Beijing) had been approved for limited use.
Normally, candidate vaccines must pass three major stages of development: preclinical study, clinical trial (phases I, II, and III), and finally, approval and licensing.
First is the preclinical study: the vaccine prototype is tested in lab animals like rats or monkeys. The aim is to determine if the prototype produces an immune response. The preclinical study lasts from 1.5 to 2.5 years and is a highly selective process. No more than 20 percent of vaccine prototypes pass the preclinical study to proceed to the human testing (clinical trial) stage. Many fail because the prototype does not work or does not have adequate funding.
In a preclinical study, the prototype is tested on human cells in vitro (in a lab) and then in vivo (in a living organism) in lab animals. Once in vitro testing produces an anti-infective response and does not cause excessive cell death, the study can then proceed to in vivo animal testing.
Mice are preferred for in vivo testing because they have 85 percent genetic similarity with human genes, are relatively inexpensive, and do not pose ethical issues. But there is a problem. Human genes contain the ACE2 receptor, which is the enzyme that binds with the SARS-CoV-2 that causes Covid-19 and allows it to enter the human respiratory tract to cause severe respiratory distress to the point of respiratory failure (inability to breathe). Meanwhile, mouse genes do not have the ACE2 receptor, so they can quickly expel the coronavirus. So the lab mice are genetically modified to carry the ACE2 receptor, just like humans.
Second is the clinical trial stage: the candidate vaccine is tested on human volunteers over three separate phases. In the phase I clinical trial, the candidate vaccine is given to a small number of volunteers to test its safety and the correct dose for producing an immune response. In phase II, the candidate vaccine is given to hundreds of volunteers separated into several groups according to certain characteristics to see whether the candidate vaccine different responses. In phase III, the candidate vaccine is tested on thousands of volunteers. The aim is to observe the responses in volunteers who have been infected with the virus and compare them to the responses in volunteers who are not given the candidate vaccine or are given a placebo (a substance other than the candidate vaccine).
In June, the US Food and Drug Administration (FDA) disclosed that any SARS-CoV-2 vaccine must have at least 50 percent efficacy, meaning that the vaccine must either prevent disease or reduce the severity of disease in at least 50 percent of all people who receive it. The FDA is the US counterpart of Indonesia’s BPOM and has the authority to give either a red light or a green light for the mass production and distribution of any new food or drug.
All existing vaccines have efficacy rates higher than 50 percent: The effectiveness of the varicella vaccine has an efficacy rate of 80-90 percent; the FluMist vaccine about a 70 percent efficacy rate; the meningitis vaccine, 60-70 percent; the HPV vaccine, about 70 percent; the rotavirus vaccine, about 75 percent. The pediatric combination vaccine has an efficacy rate above 90 percent.
Third is the approval stage. In this stage, each country reviews the candidate vaccine for approval or not. Once it is approved, the candidate vaccine becomes a final vaccine that can be distributed, but it must be monitored to ensure its safe and effective use in humans.
Considering this long process under normal conditions, if initial research on a Covid-19 vaccine began at the end of 2019 shortly after the Chinese government announced its first confirmed case, then the vaccine can enter mass production only at the end of 2032 (assuming a research period of 13 years). “Normal conditions” refers to sequential completion of each developmental stage, entering a new stage only on successful completion of the previous stage.
However, the Covid-19 pandemic has shattered the world order very quickly. The world economy has been devastated, millions of people have been infected, hundreds of thousands have died, and the pandemic shows no signs of subsiding. If we follow the normal research and development procedures that can take up to about 13 years, the human toll will be enormous.
Shortcutting vaccine development
The health emergency has prompted a number of countries to enter into a race against time in developing a Covid-19 vaccine by cutting as much time as possible. The goal is to complete the vaccine research in 18 months. A process that normally takes 13 years is being shortened to 18 months. It is a mission impossible. The efforts to combine the stages of vaccine development require broad collaboration involving experts at research institutions, clinical trials administrators, pharmaceutical manufacturers, and certifying authorities. A special strategy is needed to speed up vaccine development towards mass production.
First, accelerate the research. Research shouldn’t start from scratch. The main provision is the experience gained from researching the previously discovered coronaviruses, SARS (Severe Acute Respiratory Syndrome, 2002) and MERS (Middle East Respiratory Syndrome, 2012). In this way, the time dedicated to research can be reduced to 1-2 years. This stage should proceed directly to the full clinical trials without taking too much time studying Covid-19, instead being sufficiently armed with existing findings and knowledge. This process can cut 1.5 years.
Second, accelerate the clinical trial phases. The way to do this is by starting one phase while completing the previous phase. This method will cut three years from the duration. The clinical trial phases are then combined to start the phase III early (to cut 1-2 years). The final phase of the clinical trial should give the candidate vaccine to health workers and other workers on the front lines of Covid-19 management (to cut 1 year).
Third, accelerate production. This can be done by building a factory or preparing the production facilities in advance before the clinical trials are completed (to cut 3 years), and using the latest mRNA technologies (to cut 1.5 years). Finally, accelerate licensure from the usual one-year period to six months (to cut 0.5 year).
Vaccine development through production would take 13 years under normal conditions, but the above strategy of accelerating each stage in the process would cut 12 years off to just one year! If it works, it would be exceptional, and a Covid-19 vaccine could be ready as early as February 2021.
Scientists have been researching a coronavirus vaccine since the SARS (2002) and MERS (2012) outbreaks, but the majority of the research did not materialize for a variety of reasons. The ongoing Covid-19 pandemic is very destructive, far more virulent, and far more widespread than SARS and MERS. Some researchers believe that Covid-19 might eventually become an endemic, seasonal disease like the flu. This is why many scientists and pharmaceutical companies are racing to develop an effective vaccine against SARS-CoV-2, including by accelerating all phases because this is a state of emergency.
Hopefully, we will all be wiser in our responses to the arrival of the Covid-19 vaccines, both homegrown and foreign-made. These humane efforts are intended so we can immediately get our antidote to the risk of a severe coronavirus infection; because every life matters.
Djoko Santoso, Professor, Medical School, Airlangga University, Surabaya.