We Will Probably Have to Live with the Coronavirus
David Handojo Muljono, Senior Researcher, Eijkman Institute for Molecular Biology
A TEAM of researchers from the Eijkman Institute for Molecular Biology was already on its way to developing a vaccine soon after the Covid-19 pandemic struck Indonesia. They had finished the vaccine development concept by the end of March but, alas, they ran into a major obstacle in the execution of the plan. “The time needed to procure reagents and the media to breed virus stretched from a week to a month,” David Handojo Muljono, a senior researcher at the Eijkman Institute, explained during a special video interview with Tempo on November 13.
David, 66, said the team could only begin to separate and clone the genetic material of the SARs-CoV-2 virus that caused the Covid-19 in May. He added that since the domestic production was not yet feasible, it was reasonable for the government to seek vaccines from overseas including through cooperation with China-based Sinovac Biotech Ltd. “There’s a vaccine almost ready so we bought and tested it. There’s nothing wrong with it,” said the clinician and infectious disease expert who is also the deputy head of Eijkman Institute for translational research.
The Eijkman Institute and the Indonesian Institute of Sciences (LIPI) are working with four state universities, namely the University of Indonesia, Bandung Institute of Technology, Gadjah Mada University, and Airlangga University, to develop Indonesia’s own antidote named the Red and White vaccine. Each institute uses its own method. For instance, Eijkman is developing vaccine seeds using the recombinant protein technology but did not abandon the whole (inactivated) virus platform. Eijkman’s research team is also developing a technology to measure antibodies formed after vaccination.
To Tempo reporters Sapto Yunus, Mahardika Satria Hadi, Dody Hidayat, Abdul Manan, and Nur Alfiyah, this Eijkman’s hepatitis expert explained about various matters, from the challenges encountered in Covid-19 vaccine development to the virus mutation. David is also the leader of the national team researching the convalescent plasma therapy for Covid-19 patients.
You and the Eijkman team are involved in the development of the Red and White vaccine. How is it progressing?
It’s running according to the schedule. The process began with the selection of the type of vaccine. Some use whole viruses, some use part of the genetic materials of the virus or some viral vectors. The one that uses the whole virus is easier: the virus just needs to be purified, inactivated and weakened. That is Sinovac’s vaccine. For Red and White, we are developing a recombinant protein but we don’t leave the whole virus platform.
What is the difference between the whole virus and the recombinant protein platforms?
The recombinant DNA (deoxyribonucleic acid) technology cuts the antigenic protein of the virus capable of stimulating antibody production (in humans). So not the whole virus is used. Other types of vaccines generally use the entire content of the virus. Red and White only uses genetic fragments of the virus useful to form antibodies and safe reaction in humans.
Why the recombinant DNA technology?
First, we use the virus samples collected in Indonesia, not imported. Second, we use a more advanced technology that only requires useful genetic fragments of the virus. From there an antigen is created, removed and then deposited on the vector which will produce a protein similar to the coronavirus spike protein. Like a lock and the key, the recombinant technology seeks to strike the spike protein as a keyhole. So, the key cannot go in. And it creates antibodies against the lock only so our body is not stimulated to produce excessive antibodies.
What is the rationale behind the use of the virus strains found in Indonesia?
The virus will adapt itself every time it infects humans of certain ethnicities. By using the strains found in Indonesia, we hope to find the right vaccine that responds accordingly to the antigenic characteristics (of the virus). Figuratively speaking, it will be a better fitting key.
What are the advantages of the recombinant protein technology?
If the virus mutates, all we need to do is to replace it. The source is right here. Mutation is a normal occurrence. Viruses also want to live so they alter themselves to adapt itself to the surroundings. From molecular studies, mutation does not occur in the key areas where the coronavirus enters human body. But if it does, we already have the technology. We just have to make another genetic sequence based on the mutation. We start all over again and do another clinical trial using the same technology and the system we already have.
How do you know if the virus is mutating?
From the whole genome sequencing at the GISAID data bank regarding the virus’s journey from Wuhan (China) towards the West or the East. It has adapted itself throughout the journey after infecting a million people. Now it already has many clades: L, S, and three Gs. These changes should be constantly followed via molecular surveillance just like for malaria or tuberculosis. Biomolecular researchers around the world are monitoring the developments monthly.
What did we learn from the mutations of the influenza viruses?
To anticipate mutations in flu, the World Health Organization (WHO) stipulates that vaccines be updated every two years. We have to keep track of the virus’ mutations via molecular surveillance. I proposed a consortium to be set up perhaps by the research and technology minister. The Eijkman Institute, the Airlangga University, LIPI and the health ministry’s development and research agency can do the job.
What should be watched out from the mutations of SARS-CoV-2?
Mutations in the virus’ spikes should be given attention but so far spikes are more stable. There are around 614 mutations but they don’t occur in the receptor-binding domain. It’s just that the virus’ behavior has changed and it now grows faster and more efficiently. The infection rate is also reportedly higher.
How about the virulence of the virus?
Experts in the Europe and other countries have observed that it hasn’t changed as of now. So, mutation has not made it more virulent.
What caused the SARS-CoV-2 virus to grow so rapidly?
Because it spreads so fast infecting a lot of people. As regards fatality, SARS is more deadly with the 30 percent fatality rate. So is Ebola. According to the theory of severity, the more virulent a given disease is like Ebola and MERS, the higher the mortality rate is but the spread can be stalled as patients died faster. For Covid-19 virus which needs an incubation period, those infected can still be mobile and infect others during the incubation and the onset of the disease.
Experts could not predict when the Covid-19 will end. From your experience of handling communicable diseases, how long will the SARS-CoV-2 virus live on?
A lot of people believe that this virus will linger on. As it becomes less ferocious, it will be able to survive longer. The more it becomes like a flu virus, the more durable it will be. That is the central dogma of pandemics. We probably have to live with it like we do with hepatitis or flu.
In the past, some initially deadly viruses eventually disappeared into thin air before vaccines were found.
If what you mean is the viruses like avian flu virus, I don’t think the Covid-19 will disappear in the near future as the cases continue to rise. Vaccines are still needed to lessen fear and to bring the economy back to life. The process is expedited so as to give confidence to people that they have the immunity.
Does the research team plan to expedite the development of the Red and White vaccine before the virus becomes weaker?
We are already committed to develop it but we at the upstream needed time. Meanwhile there is already a nearly finished vaccine available. Well, so it was procured. When we are already successful, then we don’t have to import it anymore.
Is it true that the clinical trial of the Red and White vaccine will begin in early 2021?
Yes, the first phase. We’ve started with the pre-clinical phase involving the Food and Drug Monitoring Agency (BPOM) as well as the Indonesian Ulema Council. We are not waiting until the vaccine is half-finished to involve them to save time.
David Handojo Muljono giving an introduction speech at the Kickoff Meeting of Clinical Trial of Convalescent Plasma as a Covid-19 Additional Therapy event at the Health Research and Development’s Public Service Building, last September. Facebook.com/Health reseacrh and development center’s Resources & Health service
How far have you progressed with this phase?
Around 70 to 75 percent of the pre-clinical stage. Once it passes as a candidate, we will hand it over to Bio Farma.
Developing it locally using the locally sourced virus material, will it be cheaper to produce the Red and White vaccine?
Being a genetic material, it can be developed any time. It will be cheaper for sure and more can be produced. Nothing needs to be imported. We are also developing technologies. As regards suitability, I cannot say the vaccine is good or bad, but the characteristics will be more suitable for Indonesians.
Will this domestically manufactured vaccine have the same efficacy as the imported ones?
Clinical trials are standardized. We use the same guidelines used by the WHO and FDA (United States’ Food and Drug Administration).
Should the public be wary of the candidate vaccines being developed by the government?
I don’t think there’s a cause for concern. Let’s wait and see. They all will report to the BPOM which will certainly scrutinize everything. Our BPOM is quite meticulous and known for stringent control. If the BPOM passes them, I guess they should be okay.
What do you think of the phase III clinical trial process of Sinovac’s vaccine in Bandung?
Prof. Kusnandi Rusmil (head of the Covid-19 vaccine clinical trial research team from Padjadjaran University) knows better. I don’t think they hastily signed the permit so vaccination could start sooner. They would have also discussed the storage system or monitoring equipment. After the vaccine is injected, antibody levels should also be tested and monitored. The Eijkman is currently developing an antibody detection technology which is not yet available for public use at the moment.
How does it work?
It is the PRNT (plaque reduction neutralization test) technology that we’ve been using in the convalescent therapy. It can be used to check the antibody levels of Covid-19 stricken patients. That will be the first in the Southeast Asia.
Why wasn’t this method used earlier at the start of the pandemic?
PRNT is a long, difficult and costly process. That’s why we are also developing a safe, faster, easier and economical technology that can be used in the field. With the enzyme-linked immunosorbent assay as a substitute method, we can measure the level of immunity of an individual or the population.
The phase III clinical trial of Sinovac vaccine is still underway. Can the vaccine be used immediately after the clinical trial is completed?
What’s important is that the results are promptly reported to the BPOM for evaluation. The BPOM will examine all the files including data of the volunteers. They will analyze not just the trial results but also serious adverse events. There’s a list of reactions, for example, allergy. It was a randomized control trial so some got the vaccine, some placebo. The volunteers also didn’t know what they receive. But everyone is monitored. That’s the international procedure.
What are the respondents monitored for?
There is a set of criteria. Side effects, immediate effects, in addition to assessing the efficacy and serious adverse reactions. It’s just like making a new drug. They will look at the reactions or how much antibodies recipients develop or other reactions during the monitoring period.
Based on your experience and the available data, how promising is the Sinovac vaccine?
The clinical trial is run not only in Indonesia, but also in Brazil and Turkey with varying speeds. I don’t know the timing. Perhaps they will finish it earlier. It takes about three months to evaluate.
Will the BPOM need to wait for WHO’s approval to issue the vaccine license?
Of course not. The BPOM is the only one to assess. This is for local use so the distribution permit will come from the ‘BPOM’ of each country. That is the purpose of the clinical trial.
From your many years of experience in vaccine development research, has there been any vaccine given to the public for emergency reason before the research is completed?
They will adhere to the testing timeline. As far as I know, the (Sinovac) vaccine is imported in a finished packaged form. It is not packed here. We only did the randomized trial where some respondents were given the vaccine and some placebo. Everything has its timeline and they will be accountable to the public, scientific journals and the regulator, in this case the BPOM, and other institutions.
Doesn’t WHO play a role in determining vaccines for a given country?
The WHO facilitates and guides the countries but does not interfere in decision making regarding vaccines or their reliability. That is our sovereignty.
Besides being involved in the vaccine research, you also lead the team researching the convalescent plasma therapy for Covid-19 patients. Are there any prospects?
In the absence of a standard treatment, the convalescent plasma therapy seems to be an option. We have a huge patient population which we can make use of as source plasma donors. But we need a prequalification technology by which antibody levels can be checked rapidly and economically.
What is the success rate of the plasma therapy in Indonesia?
The research involving 29 hospitals is still ongoing. The clinical trial process for this is different from that of vaccine development. It takes about three months to monitor every 100 patients. We will give recommendations once the trial is complete. We still haven’t prepared the protocol yet, you see.
In the absence of drugs or vaccines, how effective is the plasma therapy to treat Covid-19 patients?
If we have vaccines, people don’t have to wait until they get sick. On the other hand, someone must be sickened first to donate his or her plasma. The key is the antibody that I mentioned before. If antibodies cannot yet be given actively through vaccination, yes, they can be given passively (via the convalescent plasma therapy). But once we have vaccines, we won’t need the plasma.
DAVID HANDOJO MULJONO | Place and Date of Birth: Magelang, Central Java, March 30, 1954 | Education: Bachelor of Medicine, Airlangga University, Surabaya (1974-1981); Master of Medicine (Internal Medicine), Airlangga University (1988-1993); Studied Hepatology at the University of Sydney, Australia (1989); PhD in Immunology and Virology, Jichi Medical University, Japan (1996-2000); Academy Professor from the Royal Netherlands Academy of Arts and Sciences and the Indonesian Academy of Sciences (2011); Extraordinary Professor, Faculty of Medicine, Hasanuddin University, Makassar (2011); Honorary Professor, University of Sydney (2014) | Career: Senior Researcher and Head of the Eijkman Institute’s Hepatitis Unit (since 1995), Head, Eijkman Institute’s Hepatitis Laboratory (since 1999), Head, Eijkman Institute’s Infectious Diseases Laboratory (since 2006), Member, Hepatitis Strategic and Technical Advisory Committee for the Director General of the World Health Organization ( 2014-2016), Deputy Head, Eijkman Institute for Translational Research (since 2014) | Awards: Ronpaku Gold Medal from the Japanese Ministry of Education (2000), Ksatria Bakti Husada Kartika from the Ministry of Health (2011), Satyalancana Karya Satya XXX from the President of the Republic of Indonesia (2012), Satria Medika Airlangga from Airlangga University (2013)