IO – October 23, 2020 marked a historic day for Indonesia with the tripartite signing for the development and production of a new type of Covid-19 vaccine, through the use of Dendritic Cells (DC). The signatories are the Health Ministry, Rama Pharma, AIVITA Biomedical Inc., Gatot Subroto Army Hospital (RSPAD), and Dr. Kariadi General Hospital in Semarang. The result of the project is known as the “ Nusantara vaccine” .
The initiator is former Health Minister, Lt. General (TNI) DR. Dr. Terawan Agus Putranto, Sp.Rad (K), and a former Director of RSPAD, is also known for his stellar academic and scientific achievements. Doctor Terawan first rose to prominence for his Digital Subtraction Angiography (DSA) method, an achievement that led him to be appointed Health Minister under the second Jokowi administration. He assumed the position for about a year.
His DSA method was deemed controversial and faced stiff opposition from the Indonesian Doctors Association (IDI) as well as the Medical Ethics Council (MKEK); so has the Nusantara vaccine, stirring up controversy since its announcement six months ago.
Since leaving the Health Ministry, Dr. Terawan has apparently become more focused and passionate about the Nusantara vaccine development. A day after the cabinet reshuffle, he was reportedly in Semarang to lead and oversee the first clinical trial of the vaccine at Dr. Kariadi General Hospital.
As of this writing, the Nusantara vaccine has been registered with the Health Ministry’s Center for Health Resources and Services Research and Development (www.ina-registry.org) and the US National Institutes of Health’s clinical trials database (www.clinicaltrials.gov). The clinical trial’s first phase, involving 27 volunteers, has been concluded, and its results published. Currently, the Nusantara vaccine candidate is undergoing its second clinical trial, in Irvine, California by AIVITA Biomedical Inc. The investigation is expected to extend from February to July 2021 and involves 175 volunteers.
If it is successful and the results are promising, it will proceed to phase three, and mass production can be carried out after gaining Food and Drug Monitoring Agency (BPOM) approval.
What is Dendritic Cell (DC) vaccine?
Dendritic cells (DCs) were discovered over a hundred years ago by German scientist Paul Langerhans, but their therapeutic potential has only been recently explored by Silberbeg and Steinman, who discovered the cells’ role in immune response. DC vaccine for prostate cancer patients was approved by the US Food and Drug Administration (FDA) in 2010, and hailed as a milestone.
This is how it works. When infected by viruses, cells will send out distress signals that the DCs will recognize through Toll-like Receptors (TLRs) and C-type Lectin Receptors (CLRs), which will then activate genes encoding interferon and proinflammatory cytokines, which will go on to activate other immune cells such as NK (Nature Killer) cells: these will kill the virus. Cytokines produced by DCs are able to stimulate NK cells without triggering a cytokine storm.
More importantly, DCs are capable of processing antigens to fight pathogens, and overpowering viruses in cells. In addition, cells that were dying from the virus can be “ingested” by DCs without infecting themselves. This collaborative work is followed by the activation of other cells, such as T-lymphocyte cell proliferation, through modulation by several receptors found on the surface of DCs. These T cells are a main defense mechanism against the virus, responsible for preventing a virus from replicating. A large number of lymphoid cells will multiply after exposure to the antigen produced by DCs in tandem with their own receptors. They can then kill virus-infected cells through the process of lysis and apoptosis induced by death receptors.
DCs will also activate antibodies produced by B lymphocytes in response to foreign antigens. In secondary lymphoid tissues, such as lymph nodes, tonsils and spleen, B cells will bind with antigens on the DCs follicles and B cells will split to form memory plasma cells. Antibodies will combine to form antigen-antibody complex, causing cell lysis. DCs present antigens, co-stimulatory molecules and more cytokine production to stimulate NK cells to kill virus-infected cells. DCs then head for the secondary lymphoid organs to activate T cells through three signals (antigen, co-stimulatory, and cytokines). Dendritic cell mobilization for Covid-19 therapy is very important, given the fact that they play an important role in inducing the host’s immune response against pathogens.
Based on research conducted on Middle East Respiratory Syndrome (MERS) coronavirus, the use of DCs can be adopted for several aspects. MERS infects T cells from peripheral blood and human lymphoid organs, including spleen and tonsils, through an induced apoptosis process in T cells. In patients who managed to recover from MERS, memory T cell responses can even be detected 6 years after infection. In in-vitro experiments, virus titers in rat lungs showed a significant decrease due to effector and CD8 T cells stimulated by cytokines. Hawigger et al found that the efficiency of the immune response from DCs-induced peptides is 100 to 1,000 times stronger than that of other non-specific peptides.
DCs also present antigens which will effectively make the vaccine safer compared to adenovirus-based vaccines, which can induce antibody and T cell-mediated responses, potentially triggering dangerous immune and inflammatory responses. This is what is often behind the failure of viral vector-based vaccines. DCs will present the antigen-antibody complex to the B lymphocytes and stimulate their proliferation and maturation to produce antibodies that can neutralize the virus and protect host cells from viral infection.
Extensive research on the potential of DCs as vaccines for Severe Acute Respiratory Syndrome (SARS) has been conducted since 2007, with the focus on finding potential antigens rapidly. Using artificial intelligence with molecular databases and immunoinformatic, Baruah and Bose in 2020 discovered the binding site for ACE2 receptors with the virus spike protein which can be developed to acquire antigens. The development of DCs-based products with autologous-allogeneic antiviral therapy is a sensible strategy. As a new method, challenges that have yet to be identified are the clinical response and uncontrollable factors in using DCs vaccine including its maturity, uniformity, quality, and safety.
However, these obstacles can be overcome using artificial intelligence to achieve more precise identification of DCs maturity level, specific antigens, and sequencing of antigen-antibody fusion proteins. This requires strict quality control and sufficient preclinical and clinical data. The potential of using DCs as a new vaccine method has yet to be fully explored until now. DCs vaccine platform has been supported by scientific evidence of its application as a cancer vaccine and other infectious diseases, such as HIV and Epstein-Barr Virus (EBV).
As the newest vaccine platform for Covid-19, DCs vaccine uses activated extracorporeal photopheresis (ECP) to induce monocytes into DCs with virus-specific antigens from viruses killed by adenovirus strain. This approach has been demonstrated by some researchers to show the ability of DCs to activate T cell responses and enhance humoral immunity.
Nusantara vaccine, a matter of nationalism
The discovery of the Nusantara vaccine platform was preceded by the development of a cancer vaccine at the Gatot Subroto Army Hospital’s Cell Cure Center, so its development as a Covid-19 candidate vaccine is not a new thing for Dr. Terawan who initiated the establishment of the center when he was the hospital director. A long-established partnership with AIVITA Biomedical Inc. has allowed Indonesia to become a pioneer in the field, which AIVITA excels at. The challenge is to find out how this platform can be developed in this country, where the problem is not so much of science-based evidence but the support from the government and agencies such as BPOM.
During his short tenure as a Health Minister, Dr. Terawan facilitated the government-academic-private sector partnership for the development of this vaccine, namely between the Health Ministry, represented by the Health Research and Development Agency (Balitbangkes), AIVITA Biomedical Inc. as the patent holder, Rama Pharma as the private sector partner, and Dr Kariadi Hospital and Diponegoro University’s Faculty of Medicine as academic partners and phase one clinical trials sites.
The success of phase one clinical trials was followed by phase two clinical trials in the United States. As BPOM in this case does not seem to have sufficient data, it questioned the validity of the phase one clinical trials and was inclined to withhold approval of its proceeding to phase two, even though it was carried out without having to gain BPOM approval in this matter.
Nusantara vaccine is a golden opportunity to increase the capacity of Indonesia’s human capital in vaccine making. This is an investment for the nation with tremendous intangible value, considered a scientific breakthrough. Indonesia’s human capital will benefit significantly from the knowledge and technology transfer and Indonesia’s global standing will increase as the seventh country able to produce and meet its own vaccine needs without having to be dependent on foreign-made vaccines.
Another advantage is that this autologous method is part of immunotherapy known as personalized or precision medicine, so the Nusantara vaccine can serve as a vessel to take Indonesia toward the age of personalized medicine, the major trend of the 1st century medical technology. Personalized medicine is a medical model that looks at each person’s genetic uniqueness as an important factor in disease management, from prevention to therapy. Personalized medicine separates people into different groups, with medical decisions, practices, interventions and products being tailored to the individual patient, based on their predicted response or risk of disease.
All parties should embrace Dr. Terawan’s initiative. As Covid-19 is battering Indonesia’s public health sector and economy, the Nusantara vaccine as a breakthrough born from ingenuity of the nation’s offspring can become an avenue for the national to escape the crisis. It can also allow the country to save money allocated for purchasing foreign-made vaccines. If Nusantara vaccine can make it to the production stage, this could be a huge revenue potential for the country in terms of forex reserves, as it can be exported globally.
Scientific evidence from collaborative, multinational research on DCs vaccine platform is a strong justification for the continued development of Nusantara vaccine. The government and related ministries/ agencies, including BPOM and the Research and Technology Ministry, should fully support its development as it can be the pride of Indonesia. It would be a shame if this promising candidate vaccine faces resistance that is political and non-scientific in nature, stoked by various vested interests with no concern for seeing the nation and its people freed from the shackle of the Covid-19 pandemic. The government only needs to throw its support behind the Nusantara vaccine development by providing necessary facilities and removing bureaucratic hurdles so it can eventually see the light of day. (Tifauzia Tyassuma)
Tifauzia Tyassuma, MD, MSc is the president of Advancing Health Literacy on Nutrition & Neuroscience Indonesia (AHLINA) Institute. She earned her Doctor of Medicine and Master’s degree in Clinical Epidemiology from Gadjah Mada University’s School of Medicine. Currently, she is undergoing a doctoral program at the University of Indonesia’s School of Medicine, with research in Nutritional Neuroscience. She is also an academic, researcher, public speaker, social and health advocate, an author of two best-selling books and a holder of a number of intellectual properties.