The issue of vaccine independence arose amid the ongoing tragedy in India, where a second, deadlier wave of COVID-29 has not only paralyzed the local health system but also frightened many other countries.
Research for the production of a domestic vaccine, namely the Red and White vaccine, continues to progress.
In a bid to smoothly get international recognition, efforts to develop a Red and White vaccine need to be immediately included in the World Health Organization website. Currently our vaccine candidate is not included in the list of 284 vaccine candidates there.
The issue of vaccine independence arose amid the ongoing tragedy in India, where a second, deadlier wave of COVID-29 has not only paralyzed the local health system but also frightened many other countries. The situation in India immediately brought two threats: namely the potential spread of malignant mutant variants from India to many countries through the travel of its citizens; and last but not least, India canceling plans to export vaccines to countries that need them.
Previously, India had committed to exporting its vaccines to countries in need, especially those that were not yet able to produce vaccines. However, after the Kumbh Mela (The Great Pitcher) ritual on the Ganges River, which resulted in a new wave of infections, more than 400,000 cases per day with the deaths of more than 4,000 people per day, the government of India immediately canceled the vaccine export plan. As a result, many countries that have not been able to produce, or are still in the process of research and development, are in a state of dismay.
Indonesia is fortunate because it has entered into import contracts with six foreign vaccine manufacturers, such as Sinovac, Moderna, AstraZeneca, Pfizer, Sinopharm and Novavax, as stated in a Health Ministerial Decree issued on Dec. 28, 2020. However, all countries in the world are lining up to get vaccines that the production capacity of all these producers has not been able to meet global needs, especially with the alarming number of cases and deaths in India.
Vaccine candidate development
Thankfully, Indonesia is one of the countries participating in the COVID-19 vaccine development research race. Indonesia is not too late because since March 2020 or three months after the Chinese government announced the emergence of the SARS-CoV-2 virus in Wuhan, the Research and Technology Ministry has been preparing a national vaccine research consortium consisting of the Eijkman Institute for Molecular Biology, Indonesian Institute of Sciences (LIPI), Airlangga University (Unair), the University of Indonesia (UI), Bandung Institute of Technology (ITB), Gadjah Mada University (UGM) and Udayana University.
April, or a month after the consortium was formed, the LIPI Center for Biotechnology Research and Eijkman immediately started research with the target of making a vaccine. Both use the recombinant protein method. In Eijkman's research, the gene encoding the protein capsule of the RNA sequence of the SARS-CoV-2 virus was taken and inserted into a vector or gene carrier called a plasmid, then inserted into a bacterial cell. This way, the vaccine can train antibodies to recognize viruses that are about to infect cells.
The LIPI research uses the gene encoding the spike protein as a whole, taking various parts of the spike, including the receptor-binding-domain (RBD). The goal is to create a variety of neutralizing antibodies that can paralyze the virus.
If it can bind to RBD, parts of RBD and its surroundings, the virus will no longer be able to infect cells. This is to answer the threat that vaccines are less effective against the latest viral mutation variants.
Unair and ITB use different methods, namely by modifying the adenovirus so that it cannot reproduce and is harmless in the human body. This modified adenovirus was used as a vector or carrier for the gene encoding the spike protein in SARS CoV-2. When the adenovirus vaccine is introduced into the body, it inserts the gene into the cells. Then, it is our own body cells that will produce the coronavirus antigen so that it will trigger the body's defense system response. If the coronavirus enters the body, our defense system has been trained to fight it.
Research at Airlangga University uses a gene isolated from a virus that infects Indonesian patients. This means that the virus isolates come from local patients, not foreign ones. Unair also designs vaccines from mutated variant genes and subunits. So, there are three vaccine designs: the whole protein design, the mutant protein and the subprotein. Thus, later we can compare the original, mutant and subunit lines. Currently, it has entered the gene cloning stage, targeted gene construction to be ready for inclusion in the adenovirus vector by the end of September, and preclinical testing on animals is targeted for November.
Udayana University (Unud) research has developed a prototype of m-RNA, a gene that carries instructions into cells that produce proteins. This method has the potential to develop vaccines more rapidly with higher purity. For preclinical testing, Unud is cooperating with Unair, which has a Bio Safety Level-3 (BSL3) lab facility.
Meanwhile, UI uses a DNA platform, which is almost the same as the m-RNA method in eliciting an immune response. The difference is, DNA vaccines must be inserted into the cell nucleus through the cell wall. When our cells divide into daughter cells, DNA can enter the nucleus of the cell. However, the problem is that most of our cells do not divide, so the cell's nuclear wall is still intact. The biggest challenge is to penetrate the cell nucleus wall and insert DNA into the cell nucleus. The DNA vaccine developed by UI is said to have entered the preclinical stage.
Spirit within limitations
Vaccine development research is a complex work, but the mass production process is no less complex. From the supply of vaccine ingredients, the production process, bottling, packaging, labeling and distribution (which need a special place) to registry administration, everything must be carried out in a safe environment. It takes no less than 200 items and jobs until the vaccine is ready to be injected.
For this reason, this stage of mass production is handed over to institutions that have the production and distribution facilities, human resources, legal standing and experience. In this case, it is Bio Farma, a state-owned enterprise that has long been known as a world-class vaccine producer and is recognized by WHO. However, along the way there was the involvement of PT Biotis in collaboration with Unair. The domains of LIPI, Eijkman, Unair, UI, ITB, UGM and Unud are research up to the preclinical testing stage. The next step is to enter the clinical trial phase, which involves many volunteers, in collaboration with Bio Farma, which will mass-produce the vaccine.
Eijkman and Bio Farma have since the end of February started the vaccine transition process. In this transition period, experts from Eijkman work at Bio Farma, and experts from Bio Farma work at Eijkman. The goal is to ensure the transition process goes smoothly. Bio Farma's experts study the process of developing vaccine seeds in Eijkman, and Eijkman's experts ensure that the system at Bio Farma is ready to continue the process of mass production or downstreaming, so as not to start from scratch. According to the initial target, the first stage of vaccine seeds should have been ready by now.
According to the latest news, the Red and White vaccine can only be used in early 2022. The progress is indeed slower than other vaccines that have been used by several countries. However, it's OK to be a little late; the important thing is to be able to produce national vaccines so as to reduce dependence on imports. Last year, the Research and Technology Ministry announced it would provide Rp 300 billion (US$21 million) in funds to support this Red and White vaccine research program — this is clearly not enough. Not long ago, the finance minister stated that she would provide Rp 73.3 trillion to meet the import target of 663.6 million doses of vaccines in 2021 — of course, on the condition that the prices do not increase because rich countries have started buying vaccines since the second wave of COVID-19 infections in India.
Comparing the Red and White vaccine research fund, which is only Rp 300 billion, with the vaccine import budget of Rp 73.3 trillion, it is clearly not balanced — like a drop of milk in a pot of potion.
Even so, the spirit of producing the Red and White vaccine continues to flare in order to make a national vaccine and contribute to a solution to the global pandemic.
Not on the WHO list
There is another issue, namely the transparency of the development of the Merah Putih vaccine on the global stage. On the WHO page (who.int), there is a “COVID-19 candidate vaccine landscape and tracker”.
It offers an excel file containing a list of all research on developing SARS-CoV-2 vaccines worldwide. On that page, all countries in the world, both developed and developing, record their vaccine research so that their development can be seen transparently by all citizens of the world. Here, research institutes, methods and vaccine platforms are listed, as well as explanations of the platforms.
Then, those vaccine candidates are separated based on which ones have just reached the pre-clinical stage, which ones have been clinically tested, and which ones have received emergency use permits or have already been used. The list is updated weekly. As of May 21, the document lists 101 clinical phase vaccine candidates and 183 preclinical, making a total of 284 candidates. It comes complete with platform acronyms, descriptions, types, dosages, schedules and research institutes. Famous vaccine developers are included, such as Sinovac, Novavax, Sinopharm, AstraZeneca, Moderna and Pfizer.
Thailand has listed at least three vaccine candidates that are in the preclinical stages: a DNA-based vaccine candidate with electrophoresis (electric shock) developed by the Chula Vaccine Research Center; a subunit protein-based vaccine candidate developed by a government pharmaceutical company together with Chulalongkorn University; and a candidate for a vaccine based on "virus like particle", which was developed by Mahidol University with a government-owned pharmaceutical company.
Turkey listed six candidates, all using a subunit protein platform and are being developed by five research institutes belonging to universities and one Turkish pharmaceutical company.
Surprisingly, there is absolutely no research on vaccine candidates from Indonesia on this list. The six top institutions and universities that are researching vaccine candidates using different platforms are not listed on the WHO website at all. How could this happen? Did the government, the Health Ministry or our universities and institutions not take the initiative to register their respective vaccine research at WHO? Why are our six institutions struggling to develop vaccines for research but are not registered with the WHO?
What is clear is that if the vaccine research by our six institutions is listed on the WHO website, it will certainly add to our pride for the scientists who are struggling to produce this vaccine. And when the effort to make the Red and White vaccine is truly successful, it will not be difficult to get international recognition, allowing the Red and White vaccine to take off faster and without any doubts. Let us immediately put the Red and White vaccine candidate on the WHO list.
Djoko Santoso, Professor of Medicine at Airlangga University; chairman of the East Java MUI Health Agency.
(This article was translated by Kurniawan Siswoko).
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