ABSTRACT

Starting in January 2020, the 2019 novel coronavirus (2019-nCoV) infection outbreak in China has spread progressively to the world and WHO declared it a public health emergency that was of international concern. Indonesia is one among the countries in Asia affected by this outbreak. The World Health Organization (WHO) then on 11 February 2020, announced a new name for epidemic diseases caused by the 2019- novel coronavirus as coronavirus disease (COVID-19). Stated by the Badan Nasional Penanggulangan Bencana (BNPB) as disaster emergency since April 13th 2020 then the status has been continuing until now. Rather than find out the conventional therapeutic methods, all countries relies on vaccines to prevent disease in large populations. Described in this report, Genius MG-1 oral vaccine, which was considered as a “whole inactivated RNA-sourced material” SARS-CoV-2 Based Vaccine group, has been given as supportive treatment to a 47- year-old male who had suffered from Severe Covid-19 respiratory symptoms. Went to ED with mild fever, and body aches thought as a result of sports activity, the patient experienced very progressive severe breathing problems days after. Previously admitted to common ward diagnosed as common flu he was moved to the Isolation Room for Covid-19 after positive results of Rapid Diagnostic Test (RDT) and Rt-PCR. His X-ray examination also showed progressive worsened of bronchopneumonia. The use of High Flow Nasal Cannule (HFNC) adjusted carefully to maintain SpO2 > 95% helped the patient of his respiratory problem. As adjuvant for recommended treatments we decided to make use of novel Genius MG-1 oral vaccine. The next day after Genius MG-1 administration the setting of HFNC easily decreased and adjusted and he showed big improvement on his dyspnea symptoms. While on this case the administration of Genius MG-1 have shown to be effective to improve patient symptomps, further studies are needed to establish more effective dosing, treatment course, and convincing the absence of side effects of this novel oral vaccine.
keywords : oral vaccine, RNA, Covid-19 vaccine, Covid-19 antibody

1. INTRODUCTION
On early Pebruary, 2021 as other countries in the world, Indonesia is still experiencing the COVID-19 outbreak under the situation of pandemic emergency. This disaster emergency status was stated by the Badan Nasional Penanggulangan Bencana (BNPB) since April 13th 2020 and has been continuing until now.1

COVID-19 has been found to be the cause of severe pneumonia and acute respiratory distress syndrome (ARDS) with a significantly high mortality rate. 2 The virus is typically rapidly spread from one person to another via respiratory droplets produced during coughing and sneezing. It is considered most contagious when people are symptomatic, although transmission may be possible before symptoms showed in patients. Time from exposure and symptom onset is generally between 2 and 14 days, with an average of five days. Common symptoms include fever, cough, sneezing and dyspnea or shortness of breath. Complications may include pneumonia, throat pain and acute respiratory distress syndrome. As of now there are no approved treatments for this viral pandemic. Currently, there is no specific antiviral treatment or vaccine; efforts consist of symptom abolition supportive therapy.

According to the World Health Organization, there are 207,855 confirmed cases and 8648 deaths from COVID-19 as of March 19, 2020 and rapidly increasing.3

In this report we present a case of middle age male found to be positive for the COVID-19, presented with fever, cough, dyspnea, and shortness of breath and was requiring high flow of oxygen nasal cannule settings and as his improvement after the use of Genius MG-1 whole inactivated oral vaccine based on RNA-sourced material.

2. CASE SUMMARY
A 47-year-old male presented to the emergency department (ED) with main complain a fever and whole body aches since a day before, he was thought it was come from his previous hard sport activity. He claimed that did not have any direct contact with people who suffered Covid-19. By then he was admitting to the ward to have his treatment for un specific fever.

On January 24th, 2021, as standard procedure for all patients with history of fever, he was undergone Rapid Diagnostic Test (RDT) for Covid-19, and the results showed reactive Ig M and positive antigent. The day after the patient also confirmed after a positive polymerase chain reaction (PCR) test. The patient then was designated as a suspicious for Covid-19 and then moved to the Isolation Room. In this point, his vital signs showed nothing except mild fever. His BP 110/79 mmHg, HR 78 beats/minute, RR 20 breaths/minute, temperature 37,9⁰C, and Peripheral Oxygen Saturation (SpO2) 99% breathing room air. Chest X-ray examination didn’t show any signs of bronchopneumonia (Figure 1a). Management of patient included given O2 3 lpm through nasal cannule, infusion of sodium chloride (Na Cl) 0.9% 500 cc in amount of 28 drops per minute, injection of Heparin 5000 IU, 2×75 mg Oseltamivir orally, 1×750 mg Levofloxacin orally, and 1 gram Paracetamol infusion if needed. This therapy was continued until January 26th, 2021.

During the treatment period, the patient showed a gradual increase in symptom severity starting from day 4, on January 26th, 2021, when the patient began to complain of a dry cough and a mild breathing difficulty. At this time, he was still given oxygen through a nasal cannula 3 liters / minute as previous treatment, however on the following morning of January 28th, 2021, the cough and dyspnea symptoms got worsened. The administration of nasal oxygen cannula 3 liters / minute is no longer sufficient and the oxygen saturation (SpO2) has decreased to 93%. The patient then given O2 8 lpm through Non Rebreathing Mask (NRM) to meet the need of his oxygenation and achieved SpO2 higher than 95%. High Flow Nasal Cannule (HFNC) was applied to keep the oxygen saturation sufficient to supply the oxygen demand. High flow oxygen up to 60 liter per minute (lpm) adjusted gradually to produce SpO2 95 – 98%. Physical exam was significant for a dry cough and showed bilateral rales on auscultation of the lung fields. A chest X-ray (Fig. 1b) was performed showing bilateral opacities throughout the lung fields with predominance of the lower lung lobes and corresponded for possible pneumonia with suspected COVID-19. Low molecular weight heparin (LMWH) at a dose of 0,4 ml was administered subcutaneously twice a day together with heparin nebulizer 3 cc every 6 hours as a prophylaxis for prothrombotic events. However the patient got much worsened and two days after the patient’s condition continued deteriorated. He became hypoxic to 85% oxygen saturation while on HFNC so the flow increased more progressively up to 65 lpm. An arterial blood gas test showed a pH of 7.43, PCO2: 32, PO2: 69, HCO3: 24, lactate: 1, and oxygen saturation of 94%.

Chest X-ray examinations showed a significant development starting from the time the patient was examined on day 3 of treatment, 25th January, 2021. At this point the radiological images have not show any significant abnormalities yet (Fig. 1a). However, only 3 days later, on 28th January, 2021, while the patient complained of cough and dyspnea symptoms, the X-ray examination showed clearly the typical signs of bronchopneumonia (Fig. 1b). Likewise, when the X-ray examination was done four days later, on 1st February, 2021, the signs of bronchopneumonia was still very clearly depicted (Fig. 1c).

The worsened dry cough and dyspnea clinical symptoms showed by increased respiratory rate (RR), reached 32 breaths/minute, and decreased oxygen saturation (SpO2). With HFNC oxygen assistance SpO2 maintained > 95%, but it required a very high oxygen flow up to 65 lpm. At that time it was decided to try other therapy modalities out of the standard therapy had been given so far during the treatment days.

On January 4th, 2021 the patient was given oral Genius MG-1 as supportive therapeutic twice a day on the morning and evening just 1 hour before meals. Genius MG-1 is an oral vaccine based on wholly inactivated RNA-sourced material technology, manufactured by Pravitna Genius Sel LLC in Ukraine. As others vaccines, this Genius MG-1 trains the body’s immune system to recognize some signature viral protein called an antigen. This vaccine advantage was offering the simplicity of use via oral intake as capsules.

On the next fourth day, the patient started to be quite stable and just required lower flow of HFNC setting. For the following days the patient showed great improvement in his general condition. On the 25th day of his hospitalization, his polymerase chain reaction (PCR) test showed negative result and he was considered clinically recovered and discharged with follow-up on an outpatient basis.

During the period of treatment, specific blood laboratory tests were also carried out to analyze and estimate the progress and severity of the Covid-19 disease. Several items examined in the early days of treatment confirmed the body general inflammatory processes, two of them were elevated white blood cells (leukocytes) and quantitative CRP for Covid-19. In addition, there was also a decrease in lymphocyte levels and an increase in D-Dimer levels in the blood. All the results of these laboratory tests were in line with the worsened clinical symptoms of the patient. However, when the critical periods began to pass and the patient finally on progress of improvement, all of these laboratory variables also returned to the standard values for healthy people (Table. 2).

3. DISCUSSION
In this report, we describe the clinical symptoms, management, therapy, and progression of a 47 year-old male case that allowed for recovery from COVID-19. On admission, since there was no specific signs lead to the Covid-19 diagnosis, we gave only the standard of care for common flu patients in this hospital. But after the massive progression of symptoms started then critical status assessment, and clinical management with oxygen by the high flow nasal canula (HFNC) for severe cases included. In this case report, acute respiratory failure triggered by COVID-19 was promptly addressed.

The Covid-19 virus is typically rapidly spread from one person to another via respiratory droplets produced during coughing and sneezing. It is considered most contagious when people are symptomatic, although transmission may be possible before symptoms show in patients. People with COVID19 have had a wide range of symptoms reported ranging from mild symptoms to severe illness. Common symptoms include fever, cough, sneezing and dyspnea (shortness of breath) or breathing difficulty, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose nausea or vomiting, and even diarrheam, while complications may include pneumonia, throat pain and acute respiratory distress syndrome.4,5 Time from exposure and symptom onset is generally between 2 and 14 days, with an average of five days. By a wide variety of initial symptoms, patients can range from asymptomatic infections to severe disease. Approximately 14% (13.8%, n = 44,672) of patients develop severe disease, which requires hospitalization and oxygen support, and around 5% require intensive care unit management.6 Despite being highly contagious, a significant portion of people infected with COVID-19 don’t experience any symptoms. Those people who do exhibit symptoms most commonly experienced dry cough, fever and difficulty breathing. However, there are also a myriad of atypical symptoms that may be under-reported.7 The most commonly documented atypical symptoms include malaise, disorientation or exhaustion. A significant proportion of patients also experience the loss of smell and taste. About 10 percent of COVID-19 patients have gastrointestinal symptoms, such as diarrhea, vomiting and abdominal pain. Our patient fisrtly appeared on ED with nothing critical symptoms except fever and body aches. In addition, he also reported of had has no contact with suspected Covid-19 patients days before. That made very reasonable to admitt the patient to the ward without the suspicions of Covid-19.

COVID-19 can provisionally be diagnosed on the basis of symptoms and confirmed by reverse transcription polymerase chain reaction (RT-PCR) testing of infected secretions or CT imaging of the chest.8,9 However a study conducted by Xuanyang et al., used X-ray images to distinguish SARS-CoV and typical pneumonia. Using a chest X-ray is a faster, easier, cheaper, and less harmful method than CTscan.10 A typical picture of COVID-19 bronchopneumonia showed by the presence of patches or infiltrates in the basal and peripheral, lower lobes, and multilobar supported by the result of the rRT-PCR examination to have definitive diagnosis of COVID-19. This patient has undergone Rapid Diagnostic Test (RDT) for Covid-19, and the results showed reactive Ig M and positive antigent and the day after he also confirmed after a positive reverse transcription polymerase chain reaction (RT-PCR) test. The patient then was designated as a suspicious for Covid-19 and moved to the Isolation Room.

COVID-19 is the cause of severe viral pneumonia rapidly leading to ARDS. In a case series of 135 patients, Wan et al reported 88.9% of patients presented with a fever and 76.5% had a cough. Fatigue and myalgias (32.5%), headache (17.7%), and dyspnea (13.3%) were less commonly reported.11 Some of these symptoms were also found on presentation with our patient. The fever and myalgia or body aches disappeared shortly after he was in ward, but it suddenly changed with a very proggresive dry cough and dyspnea. Dealing with the severity of the disease, oxygen therapy, intravenous fluids, and breathing support given careffuly adjusted to the symptoms with the target reached saturation oxygen > 95%. While 3 lpm oxygen of nasal cannule (NC) was no sufficient anymore it upgraded with NRM 8 lpm and then HFNC up to 65 lpm to achieve SPO2 < 95%. This treatment was done very carefully and proggresively since failure to promptly recognize and treat COVID-19 pneumonia may lead to an increase in mortality.

Blood laboratory test was also performed periodically on the patient. Laboratory results on day 3 showed 66% neutrophils and 24% lymphocytes, high neutrophil values appear while the lymphocyte values are still quite normal. The Neutrophil to Lymphocyte Ratio (NLR) is 2.75. On day 7, the Neutrophil value was 70%, lymphocytes were 12% and the NLR was 5.83. These NLR values were in line with the severity of clinical symptoms. While on day 19, when the situation was getting better, neutrophil values decreased to 63% and lymphocytes were 20%, NLR was 3.15, and much better on day 22, when the NLR value showed 1.72. NLR, known as a marker of systemic inflammation and infection, as a predictor of bacterial infection, including pneumonia. In many cases COVID-19 often found high neutrophil levels and low lymphocyte levels (lymphopenia).12,13 This parameter needed for the prognosis of infection, inflammation and some types of cancer. Neutrophils themselves serve as a defense against microbial invasion or phagocytosis. These cells have an important role in the diagnosis of inflammation and infection. Meanwhile, lymphocytes are small cells that move to inflammatory sites. Lymphocytes are also a source of immunoglobulins which are important in the body’s cellular immune response. Lymphocytes have a role to fight infections caused by viruses or bacteria. Absolute lymphopenia occurs in severe cases. The NLR value was obtained by dividing the diff count value of neutrophils divided by the diff count value of lymphocytes. To diagnose Covid-19, the NLR value has a cut off limit of 3.13.14,15,16 Besides that, high CRP of the patient on day 3 (1.95 mg/dl) also gave signs of early fase of severe inflammation. Some study showed that high CRP levels were positively correlated with the severity of lung lesion and disease severity.17 High CRP level on day 3, in this case, however reflected with chest radiograph result on 28th January, with marked bilateral infiltrates. The chest lesion was improved on day 19, which was also correlated with lower CRP levels (0.10 mg/dl).

Currently, there is still no specific antiviral treatment or vaccine has provided; efforts consist of symptom abolition supportive therapy. Depending upon the severity, oxygen therapy, intravenous fluids, and breathing support may be required.18 As adjuvant of recommended treatments in ward we decided to make use of novel Genius MG-1 oral vaccine based on RNA-sourced material wholly-inactivated vaccine technology, manufactured by Pravitna Genius Sel in Ukraine. The next day after Genius MG-1 administration the clinical symptoms such as work of breathing and SpO2 had gradually improved and he showed big improvement on HFNC setting provided to achieve SpO2 > 95%.

Compared to other types of vaccines that had already have longer acknowledgement in history, whole inactivated oral vaccine based on RNA-sourced material is a new type of vaccine to protect against infectious diseases compared to the way of other type of vaccines to trigger an immune response by putting a weakened or inactivated germ into our bodies. Not mRNA vaccines. Instead, this novel type of vaccine teach our cells how to make a protein— or even just a piece of a protein—that triggers an immune response inside our bodies. That immune response, which produces antibodies, is what protects us from getting infected if the real virus enters our bodies.

COVID-19 whole inactivated oral vaccine based on RNA-sourced material gives instructions for our cells to make a harmless piece of what is called the “spike protein.” The spike protein is found on the surface of the virus that causes COVID-19. Once the instructions (wholly inactivated RNA-sourced materials) are inside the immune cells, the cells use them to make the protein piece. After the protein piece is made, the cell breaks down the instructions and gets rid of them. Next, the cell displays the protein piece on its surface. Our immune systems recognize that the protein doesn’t belong there and begin building an immune response and making antibodies, like what happens in natural infection against COVID-19. At the end of the process, our bodies have learned how to protect against future infection. The benet of whole inactivated RNA-sourced material vaccine, like all vaccines, is those vaccinated gain this protection without ever having to risk the serious consequences of getting sick with COVID-19.

Genius MG-1 was designed as a capsule protected with special vaccines encapsulated inbiodegradable polymers coating prevented destruction inside the stomach.20,21 Biodegradable polymers, which have a tendency to undergo non-enzymatic hydrolysis under in vivo conditions, have been reported to be used as an efficient delivery system by the oral route. These chemical structures protect the antigen while passing through the stomach but allow release in a gradual manner inside the intestine.22 Generation of a successful immune response in all these cases has underlined the functionality of microcapsules as oral vaccine delivery vehicles.
Radiological image on the day of discharge showed great improvement however we believe that the lung damage caused by the Covid-19 virus was quite severe and will require time to heal. Therefore, it is recommended to continue the Genius MG-1 oral vaccine treatment until it reaches approximately 1 month from the initial administration.

4. CONCLUSION
COVID-19 is a serious infection that had caused thousands of cases of severe pneumonia, ARDS, and even death worldwide. As the number of cases and deaths from Covid-19 continued to increase, the race of development of the drug of choice treating this disease was still becoming focus of the global health care system. However, there was yet no formally approved treatment.

Meanwhile, the use of the whole inactivated RNA-sourced material vaccine as a Covid-19 preventive tool has been upgraded to be a supportive therapy, which is as an oral vaccine. Genius MG-1 is one of the product. This case report describes the effectiveness of the Genius MG-1 oral vaccine to improve clinical symptoms of a patient suffered from severe Covid-19. Further research is needed, however, to establish a more effective dosage plans, course of treatment, and ensure that there are no side effects of this oral vaccine.

REFFERENCES

1. Maharani T. Gugus Tugas Covid-19: Indonesia Masih Darurat Bencana. Accessed on May 24, 2020 https:// nasional.kompas.com/read/2020/05/22/12443631/gugustugas-covid-19-indonesia-masih-darurat-bencana.
2. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study. Lancet Respir Med 2020;8: e26.
3. World Health Organization. “Coronavirus disease (COVID-19) outbreak.” URL https://www.who.int/emergencies/diseases/novel-coronavi rus-2019 Accessed March 19, 2020.
4. A. J. Tyrrell and M. L. Bynoe. Cultivation of viruses from a high proportion of patients with colds. The Lancet, vol. 287,no. 7428, pp. 76-77, 1966.
5. www.cdc.gov>2019symptoms-testing.
6. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team and China CDC Weekly. Vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC Weekly, vol. 2, no. 8, pp. 113–122, 2020. View at: Publisher Site | Google Scholar.
7. https://www.brighamhealthonamission.org/2020/05/14/understanding-unusual-presentations-ofcovid-19.
8. “CT provides best diagnosis for COVID-19”. Science Daily. Retrieved 14 March 2020. Institute of Allergy and Infectious Diseases. Retrieved 2 May 2020.
9. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al.. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 296 (2): E32– E40. 2020. doi:10.1148/radiol.2020200642. PMC 7233399. PMID 32101510.
10. Xie X, Li X, Wan S and Gong Y. Mining X-ray images of SARS patients. Data Mining: Theory, Methodology, Techniques, and Applications, Williams, Graham J., Simoff, Simeon J. (Eds.), sISBN: 3540325476, Springer-Verlag, Berlin, Heidelberg. 2006, 282-294.
11. Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol. 2020, 1–10. DOI:10.1002/jmv.25783.
12. Curbelo J, Luquero Bueno S, Galvan-Roman JM, et al. Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio. PLoS One. 2017,12(3): e0173947.
13. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical Infectious Diseases. 2020.
14. Forget, Partice. Khalifa, Celine. Dkk. What is the normal value of the neutrophil to lymphocyte ratio ?.2017.NCBI.
15. Liu, Xuan. Shen, Yong. Dkk. Prognostic Significance of Neutrophil to Lymphocyte Ratio in Patients with Sepsis: A Prospective Observational Study. Research article: Hindawi. 2016.
16. Liu, Jingyuan. Liu, Yao. Dkk. Neutrophil to Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage. Journal: medRxiv. 2020.
17. Wang L. C-reactive protein levels in the early stage of Covid-19. Med et Maladies Infect. 2020, 50: 332-334.
18. The BMJ. Overview of novel coronavirus (2019-nCoV)—Summary of relevant conditions. The BMJ. Archived from the original on 31 January 2020. Retrieved 1 February 2020.
19. Geall AJ, Mandl CW, Ulmer JB RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013, 25: 152–159.
20. Bouvet JP, Decroix N, Pamonsinlapatham P. Stimulation of local antibody production: parenteral or mucosal vaccination? Trends Immunol 23:209–213. 2002.
21. Verdonck F, Cox E, Goddeeris BM. F4 fimbriae expressed by porcine enterotoxigenic Escherichia coli, an example of an eccentric fimbrial system. J Mol Microbiol Biotechnol. 2004, 7:155–169.
22. Shalaby W. Development of oral vaccines to stimulate mucosal and systemic immunity: barriers and novel strategies. Clin Immunol Immunopathol.1995, 74:127–134.