By. Lily Hikam*)
“I pictured myself as a virus or a cancer cell and tried to sense what it would be like.” Jonas Salk, M.D.- inventor of the Polio vaccine.
For some, the COVID-19 pandemic is a blessing in disguise. The SARS-CoV2 virus and the disease it caused, COVID-19, was so novel and severe that they wreaked havoc in almost every compartment of society. The severity and the impact of this pandemic is not nearly as frightening as the uncertainty on when or if this pandemic will ever end. For reference, the last pandemic of this scale was the Spanish influenza pandemic that lasted approximately two years, from 1918-1920. Prior to that was the Bubonic Plague which decimated 25-60% of the European continent population and lasted for seven years (1346-1353) . Adding to this uncertainty is the prospect that this virus might be here to stay and be part of our lives for the future, just like every other virus that has been unleased unto the world.
It is no wonder, then, that people are desperate for a cure, a way to mitigate this disaster, anything that can help them feel like they have some control over their lives that have been upended by a submicroscopic microorganism that can’t even replicate without a host. In times like these, countries and societies turn to their oftentimes forgotten members of society: the scientists and researchers who dedicated their lives studying these diseases to cure them and prevent their occurrence in the general population, but largely relegated to the backburner because their research is usually deemed “too expensive” or a “waste of money and time”.
The lack of understanding and appreciation to science, research and development, and the scientific method have long been a feature within the Indonesian society. Sure, we tell our kids to excel in Mathematics and hard sciences for the prestige of it and so they have an easier time navigating through the college admissions process, but that’s the extent of it. Our research and development (R&D) expenditure as percentage of GDP was reported at 0,226 % in 2018 . Compare this to the R&D expenditure of one of our closest neighbors, Malaysia, which is at 1,44% of their GDP and we are at a significant disadvantage when it comes to advancing our scientific capabilities . And it has become exceedingly obvious now more than ever with the pandemic ripping off the veneer of scientific readiness and capabilities and exposed how woefully unprepared we are in handling a large-scale disaster such as a pandemic.
In Indonesia, it is not an understatement to say that the government half-heartedly enforced a lockdown policy, and at times the policies seem paradoxical to each other (i.e. prohibitions on mudik yet re-opening tourist attractions) and economic aid is inadequate at best with people who are supposed to be on the receiving end receiving less than what was promised. Adding to this is the uncertainty on what it would take to cure this disease. The potential of a vaccine to defeat the coronavirus by way of generating herd immunity has been discussed almost as soon as the disease is declared a pandemic. Indonesia has spent the better part of the pandemic developing our own variants of vaccines, the most famous and talked about in the media is the so-called Red and White Vaccine (Vaksin Merah Putih) based on a recombinant protein technology, under the auspices of the Eijkman Institute for Molecular Biology and Bio Farma, the state-owned enterprise specializing in vaccine manufacturing. Now, this vaccine is still under pre-clinical development with an expected availability date of April 2022 .
Certainly this seems like a long ways away and for the people who are anxious for some relief, but thankfully other vaccine options are available for use now. The most widely available vaccine at the moment is the Sinovac vaccine, whose raw materials were imported to Indonesia from China and mass produced by Bio Farma. Other vaccines such as the AstraZeneca vaccine whose usage was marred by controversy regarding its halalness have also been administered.
Recently, a new type of vaccine have also been elevated to the public consciousness, but not because of its efficacy. This new vaccine variant, named Vaksin Nusantara and championed by former Minister of Health Terawan Agus Putranto, captured the public’s attention because of the way its developer tried to advertise it as the only type of vaccine that can confer lifetime immunity to its recipient .
Its name Nusantara also carried the connotation that this vaccine is developed by Indonesian scientists, when in reality it was developed by a Biotechnology company based in Irvine, CA, United States. So, what is Vaksin Nusantara? Can we even classify it as a vaccine based on how it works? And does it actually confer lifetime immunity, like the promoter claims?
The technology behind Vaksin Nusantara is the same technology underlying cancer immunotherapy. Nowadays, cancer research has been focused on training the patients’ immune system to recognize cancerous cells in the body, attack it and destroy it, with the hopes that doctors can avoid the use of medications and treatments such as chemotherapy and radiotherapy which causes significant adverse side effects on the patients.
Cancer immunotherapy ranged from engineering T-Cells to carry a chimeric antigen receptor (CAR) specific to the type of cancer cell to be targeted. These engineered T-cells, called CAR-T cells, are originally T-cells (white blood cells) obtained from the patient or a healthy donor’s bloodstream and isolated via leukocyte apheresis. These cells will then be cultured in a petri dish until their numbers are high enough before they’re transduced (given) with a vector containing the protein construct of the chimeric antigen the researcher would like the engineered T-cells to express. Once the CAR-T cells are ready, they will be injected back to the patient to start the immunotherapy process. Cancer immunotherapy using CAR-T cells have been approved by the US FDA since 2017 for treating B cell acute lymphoblastic leukemia. To date, there are five cancer immunotherapies using this method that have been approved for use by the US FDA [6,7].
In addition to engineering T-cells, cancer immunotherapy has also been expanded into looking at the possibility of engineering other cells in the immune system for the same application. Dendritic cells (DCs) whose main function is presenting an antigen (foreign materials like pieces of an invading virus) to the T-cell to induce adaptive immune response is the next hot topic in cancer immunotherapy. This DCs-based therapy, or vaccine, is the technology behind the Nusantara vaccine. The premise is simple: isolate DCs from patients, expose the DCs to to the SARS-CoV2 spike protein then inject it back to the patient so these engineered DCs will present the SARS-CoV2 spike protein to the T-cells which will activate the T-cells to target and destroy the spike protein if the individual is exposed to SARS-CoV2 later on . Sounds like a good enough strategy for a vaccine development. So what’s the problem?
For one, this DCs-based vaccine will be expensive. Very expensive. The process of isolating DCs from the body, culturing them then engineering them is an expensive and laborious process that requires a clinical laboratory facility which complies with good clinical practices (GCP) that, quite frankly, aren’t yet available in Indonesia. They also rely on culture reagents and stimulatory molecules that are not GMP-grade and are very expensive to import to Indonesia. An estimate of the cost of one of the variants of CAR-T cell therapy, Yescarta, is around $375,000 and $475,000 (approximately IDR 5.447.587.500.00 – 6.900.277.500.00) . In a time when what we need is a vaccine that will be widely available for everybody in the country, developing a therapy that is costly and exclusive is not a good approach to achieving herd immunity, rather what this will do is further highlight the gap between the haves and have-nots in this country and further demonstrate that healthcare equity is still a big issue in this country.
Two, pre-clinical data on this vaccine is very scant and limited. There hasn’t been any peer-reviewed published paper regarding the safety, efficacy and suitability of this vaccine. Instead what we have is the words of the promoter, former Minister of Health Terawan Agus Putranto, that this vaccine is the work of Indonesian scientist, which have since been proven false, and that it will elicit lifetime immunity, yet another false claim by the former Minister. The technology behind this vaccine was pioneered by an American biotechnology company called Aivita Biomedical that according to filings at ClinicalTrials.gov is one of the collaborators and have been developing this DCs-based therapy for application in cancer, not COVID-19. Filings in the ClinicalTrials.gov also showed that the study is still in phase I trial to establish whether this vaccine is safe, hence it’s a bit too early to be making claims about immunity and efficacy . There are still phases II and III to conduct which will shed more light on the efficacy and the suitability of this vaccine to help prevent COVID-19 infections.
Finally, the proposed protocol is an “autologous” mode of administration, which means that a patient’s DCs will be isolated, treated then injected back to that same patient. This is a highly personalized and exclusive approach in therapy since only one person, and usually it will be a person with significant means, wealth or prestige, who will be able to use the therapy. Contrast this with the “allogeneic” approach which includes all of the other vaccine variant wherein the same therapy can be used by as many people as possible as the therapy is not personalized for the use of one person. Once again, this approach excludes large portions of the population who have no means to use or purchase this therapy due to systemic and monetary reasons imposed upon them. This approach will just put a roadblock in the effort to achieve herd immunity in the population by eroding public trust and significantly impact pandemic recovery efforts.
In closing, I will leave you with this joke by Gus Dur that my father once told me and has a profound impact on me as a researcher ever since I first heard it. Gus Dur told the story of a Minister of Research and Technology who went to a pesantren in East Java and bragged about how his Ministry has successfully developed a rocket that could fly to the sun. Of course, this is a big achievement seeing as how the Sun is located 149.6 million km away from Earth and has a surface temperature of 5,778 Kelvin . When he told of his achievement, no one in his audience applauded or even gasped in amazement. Annoyed, he asked one of the santris why he and his peers didn’t think this was a big deal. With a shrug, the santri answered “All you have to do is fly the rocket after Maghrib, right? What’s the big deal?” The moral of this Gusdurian joke is that it doesn’t matter how technologically advanced or how cutting edge your research is if your country and your people can’t benefit from it. It would have been a waste of energy and resources if your research doesn’t bring something beneficial for your people and only serve to advance a political cause or personal goals. It is easy to get lost in the scientific pursuit of research just for the sake of research, that sometimes it’s good to reflect on how our works will impact others.
*) PhD in Biomedical Science, University of California, Irvine, USA
Srivastava S, Riddell SR (August 2015). "Engineering CAR-T cells: Design concepts". Trends in Immunology. 36 (8): 494-502. doi:10.1016/j.it.2015.06.004. PMC 4746114. PMID 26169254.
Sadelain M, Brentjens R, Rivière I (April 2013). "The basic principles of chimeric antigen receptor design". Cancer Discovery. 3 (4): 388–98. doi:10.1158/2159-8290.CD-12-0548. PMC 3667586. PMID 23550147.
Saadeldin MK, Abdel-Aziz AK, Abdellatif A. Dendritic cell vaccine immunotherapy; the beginning of the end of cancer and COVID-19. A hypothesis. Med Hypotheses. 2021 Jan;146:110365. doi: 10.1016/j.mehy.2020.110365. Epub 2020 Nov 9. PMID: 33221134; PMCID: PMC7836805.
Lyman, Gary H.; Nguyen, Andy; Snyder, Sophie; Gitlin, Matthew; Chung, Karen C. (2020-04-06). "Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma". JAMA Network Open. 3 (4). doi:10.1001/jamanetworkopen.2020.2072. ISSN 2574-3805. PMC 7136832. PMID 32250433.
Williams, D.R. (1 July 2013). "Sun Fact Sheet". NASA Goddard Space Flight Center. Archived from the original on 15 July 2010. Retrieved 12 August 2013.