Covid-19 : Epidemiological data, safeguards and medical research advances in Singapore

Since Covid-19 outbreak in December 2019, the international scientific community’s work has allowed very rapid advances in the knowledge of this new atypical pneumonia. In Singapore, the National Center for Infectious Diseases (NCID) immediately deployed a team of researchers and clinicians to provide rapid responses with regards to diagnoses and clinical profiles. Among them, the Singapore Immunology Network (SIgN), an institute of the Agency for Science Technology And Research (A-STAR). With participation of Laurent Renia – SIgN Executive Director, Sebastien Teissier – A-STAR Virologist, Clotilde El Guerche-Seblain – Influenza vaccine Epidemiologist / Asia Pacific Sanofi-Pasteur, this article provides an update of the Covid-19 situation and an overview of the main current research topics held in Singapore.

Context

The coronavirus that causes Covid-19 disease belongs to the same family of RNA 1. viruses as the Severe Acute Respiratory Syndrome (SARS-CoV), which caused the SARS epidemic in 2003 (Fig.3). The official name SARS-CoV-2 has been chosen on February 11, 2020, by the International Committee on Taxonomy of Viruses (ICTV). The World Health Organization (WHO) has declared the Covid-19 epidemic a public health emergency of international concern on January 30, 2020; it has been stated as a pandemic on March 11, 2020.

1. Ribonucleic acid (RNA): support for genetic information of coronaviruses and other microorganisms. In plants and animals, genetic information is carried by deoxyribonucleic acid (DNA), which is itself transcribed into RNA before being expressed in the body.

Figure 1 : Coupe schématique du SARS-CoV-2 (Commons.wikimedia.org)

Features of Covid-19

The first symptoms of Covid-19 are fever, fatigue and a dry cough. The infection is also characterized by other atypical and more random symptoms, such as loss of taste and smell, digestive disorders, conjunctivitis, rashes, vascular disorders (redness of the face and extremities, hives) (1)(2). The incubation period is the time between infection and disease symptoms onset. The WHO currently estimates it to be 1 to 14 days, most often around 5 days. The risk of the disease to turn into severe symptoms (eg breathing difficulties) is higher for immunocompromised people, patients with cardiovascular diseases, autoimmune diseases, aged over 60. Women, whose immune systems are generally stronger than men’s, as well as O blood group persons, appear to be less sensitive to Covid-19 (3).

Epidemiological data

The SARS-CoV-2 coronavirus that causes Covid-19 is similar to those found in wild animals, such as bats, which are likely to be the disease reservoir (4). Covid-19 would therefore be a zoonosis, a disease that can be transmitted from animals to humans. First detected in Wuhan, in the Chinese province of Hubei, SARS-CoV-2 has gradually spread over the 5 inhabited continents (Fig.2). The transmission rate estimate, R0 or basic reproductive number, varies from one study to another; it has been approximated at 2.6 in Japan (5) and 5.7 in China (6). An R0 of 5.7 means that an infected person can potentially infect between 5 and 6 others. The estimated R0 of Covid-19 may be higher than that of influenza (1.3), SARS-CoV (2-4), MERS (2.5), but much lower than that of measles (12-18)(7). As for the severity of the virus, it varies from country to country. In China, on February 11, 2020, out of a total number of 44,672 cases, 13.8% were hospitalized for severe symptoms and 5% were admitted to intensive care unit (ICU) (8). The case fatality ratio (CFR), which differs according to studies and countries, is strongly linked to population age, healthcare supply and system capacity to handle Covid-19 patients. By the end of March, estimated at 1.3% in South Korea, the CFR was 9.5% in Italy, 7.9% in Iran, 6.6% in Spain and 4.0% in China (9) (Fig.3).

Controlling the epidemic in Singapore

Without any vaccine or treatment, field data show that it is important to set up individual safeguards such as wearing a mask or regular hand washing, in order to contain the epidemic. On the other hand, preserving the healthcare system capacity to take care of the sick will avoid its saturation. With the community cases increase reported over the last weeks, first due to imported cases and the emergence of clusters, Singapore has implemented measures such as systematic testing of symptomatic people, borders closures, clusters identification, contact tracing, quarantine of potentially contaminated people, reduction of interactions between individuals, and the “circuit breaker”, which is a more stringent measure. The fundamental approach chosen by Singapore is to detect cases as quickly as possible, isolate confirmed cases and cut community transmission.

Figure 3

Molecular screening test

A-STAR quickly developed for Singapore a molecular test to identify the virus from nasal and oral swabs. This test is based on the Polymerization Chain Reaction (PCR). Detection of pathogen is obtained by amplification of known genetic sequences of the virus. This type of very powerful test is also very sensitive. It requires advanced equipment and professional technicians. Indeed, the conditions surrounding the collection and handling of the samples must be extremely sterile (Fig.4). The PCR results are obtained between 2h our 4h (Fig.5).

Figure 4 : Tubes of PCR (pxfuel.com)

Figure 5 : PCR detection and amplification of genetic sequences (commons.wkimedia.org)

Immunological screening test

A-STAR is currently working on a method that aims to measure the exposure rate to Covid-19. It is an immunological test based on individuals’ antigen-antibody response. Antibodies, also called immunoglobulins (Ig), are produced by the immune system after a pathogenic attack (Fig.6). There are several types of Ig, including the following : Ig M, produced during infection; Ig G and A, which keep in memory the “identity” of the pathogen and constitute “acquired immunity”. Knowing the types of a population’s antibodies, will allow the identification of asymptomatic people : recently contaminated and possibly contagious (carriers of Ig M); immunized and non-contagious or having been exposed to the virus more than 1 week ago (carriers of Ig G or A). This test could be considered into at-risk groups, such as hospital staff, and could lead to the implementation of new protective measures. This instant response screening will be performed on a fingertip blood drop.

Figure 6 : Antigen-Antibodies reaction scheme

Drug treatment research

When Covid-19 has drifted into severe symptoms, the patient’s viral load has dropped to almost zero. At this time, retroviral drugs are no longer useful. The immune system gets out of control and creates a severe form of the infection. It is therefore necessary to precisely define the best time window for retroviral drugs and for those acting on the immune system. A-STAR teams consequently focus their research on markers identification (eg immunological mediators such as cytokines, molecules secreted by leukocytes “white blood cells”) or other specific cells of each phase, in order to be able to offer the most appropriate drugs according to the disease stage. Many antiviral (eg HIV) and anti-disease (eg cancer) drugs are currently being tested.

SARS-CoV-2 mutations

Researchers have identified 3 lines of SARS-CoV-2. Each of them is capable of mutating over time, and creating forms of SARS-CoV-2 of variable virulence. It is not yet known whether the immunity acquired after infection with one of these forms protects against the others. If not, that could explain why some people relapse a few weeks after healing. A vaccine is currently under development in the laboratories of DUKE-NUS Medical School in Singapore. It will likely be developed using the conserved parts of the virus, those which do not mutate.

New treatments authorizations

A new treatment’s registration and approval always need clinical trials which aim at proving: the drug safety, its efficiency and side effects. The relevance of these trials is directly based upon the number of patients involved. Furthermore, we know that some drugs are efficient on certain types of populations and not on others (eg Asians versus Caucasians). Conducting these trials will help identify these peculiarities. With most of the tested drugs already being registered in many countries, their approval process for Covid-19 treatment will be accelerated. This will take longer for new drugs that are not yet registered, due to the preliminary safety trials. Several clinical trials are currently underway in Singapore, throughout Asia, Europe and the USA. In Singapore, the approval applications will be submitted to the Health Sciences Authority (HSA).

State-of-the-art techniques available to humanity today have enabled an unprecedented coalition of the international community in the fight against Covid-19 pandemic. Global containment measures are expected to significantly limit the disease spread. This step will help save a precious time for healthcare systems and medical research advances.

References :

(1) World Health Organization. Maladie à coronavirus 2019 (COVID-19) : questions-réponses [read on April 17, 2020]. Available here.

(2) Syndicat National des Dermatologues Vénérologues. Press release [published on April 6, 2020]. Available here.

(3) Zhao J. and al. Relationship between the ABO blood group and the Covid-19 susceptibility, Southern University or Science and Technology, Shenzhen, China [published on March 27, 2020]. Available here.

(4) Kangpeng X. and al. Isolation and characterization of 2019-nCoV-like coronavirus from Malayan pangolins. College of veterinary medicine, South China Agricultural University, Guangzhou, China. [published on February 20, 2020]. Available here.

(5) Kuniya T. Prediction of the Epidemic Peak of Coronavirus, Graduate School of System Informatics, Kobe University, Japan. Disease in Japan, 2020. Journal of Clinical Medicine, 9(3), 789. Available here.

(6) Sanche S. and al. High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. Emerging Infectious Diseases Journal, Vol 26, July 2020 (Early release). Available here.

(7) Sciences et Avenir Magazine [online]. Incubation, contagiosité, mortalité… les mots qui comptent pour décrire le coronavirus Covid-19 [published on February 26, 2020]. Available here.

(8) Statista. Study: Majority of coronavirus cases are mild [published on February 18, 2020]. Available here.

(9) World Health Organization. Coronavirus disease 2019 (COVID-19) – Situation report [published on April 19, 2020]. Available here.