📰 The U.S. freeze on WHO
How will the American President’s suspension of funds to the World Health Organization in the middleof a pandemic impact its work?
•The story so far: As the toll from the COVID-19 pandemic rose across much of the world, the United States President Donald Trump became more strident in his criticism of the role of the World Health Organization (WHO). On April 7, Mr. Trump tweeted that WHO “really blew it” and that the organisation was “very China centric”, this despite it being largely funded by the U.S. On Tuesday, Mr. Trump said he was halting funding to WHO pending a review. He accused WHO of mismanaging the COVID-19 crisis and said it had failed to vet information and share it in a timely and transparent manner. He told a news conference at the White House, “... I am directing my administration to halt funding while a review is conducted to assess the World Health Organization’s role in severely mismanaging and covering up the spread of the coronavirus.”
When and why was WHO set up?
•It is important to understand the context in which WHO functions to understand the current situation around its funding. WHO, a United Nations agency created in 1948, is headquartered in Geneva, and was founded to coordinate and direct the UN’s global health effort. It has no authority over its 194-member countries and, as is typical for UN agencies, depends on member contributions to carry out its work. Also, as is often the case with UN agencies, WHO is not immune to political motivations and an inertia that often comes with large bureaucracies. Yet, in this instance, critics and several public health academics have said that Mr. Trump’s attack of the organisation is misplaced.
Was WHO slow in alerting the world about COVID-19?
•It took till about the middle of January for WHO to suggest human-to-human transmission of the virus, toeing the China line for the first few weeks of the year, as per reports.
•Even then, in the first two weeks of the year and two weeks after it was notified of the virus, WHO had qualified its statement by saying there was “no clear evidence” of such transmission, The Washington Post reported. The U.S. was formally notified by China on January 3 of the coronavirus outbreak. Additionally, as early as January 10 and 11, WHO had put out guidance notes on the virus, according to The Guardian .
•China locked down the city of Wuhan on January 23. On January 23, WHO Director General Tedros Adhanom Ghebreyesus warned that while the emergency was for China and not for the world, it had the potential to become global in scale. The body’s experts were divided on whether or not there was a global emergency at the time, as per reports, and it took until January 30 for them to conclude deliberations and declare a global emergency.
•Yet, nearly a month later, on February 25, Mr. Trump tweeted that the coronavirus in the U.S. was “very much under control.” It was only on March 13 that he declared a national emergency over the coronavirus.
How much does the U.S. give WHO?
•The U.S. is the WHO’s largest contributor. The organisation’s funding is of two types — assessments or member dues and voluntary contributions. The total funds for the 2020-2021 biennium included $957 million in assessments and $4.9 billion in voluntary contributions.
•Over the last decade, the U.S.’s assessed contributions have been in the $107-$119 million range while voluntary contributions have been in the $102-$402 million range, according to the Kaiser Family Foundation, a health-focused non-profit.
•For the 2018 and 2019 biennium, the U.S. contributed about 20% of WHO’s budget, according to a National Public Radio (NPR) report. This money went as assessment fees ($237 million) or pledges towards programmes (over $656 million) from voluntary contributions. The major share of the U.S. programmatic funding went towards polio eradication ($158 million), increasing access to essential health and human services ($100 million) and vaccine-preventable disease ($44 million), according to the NPR.
Will the U.S.’s stand affect WHO’s functioning?
•The short answer is, yes, a funding freeze is highly likely to negatively impact WHO’s functioning for a short while at least, given the significant contribution the U.S. makes. However, we do not yet know what the impact will be and for how long.
•Additionally, it is unclear if Mr. Trump has the authority to withhold funding that has already been committed. Congressional Democrats have said that he does not have this authority and is criticising WHO as a means to deflect criticism of how he has handled the crisis. The U.S. has around 700,000 known cases of COVID-19 over 35,000 deaths due to the disease.
•Dr. Tedros has asked countries to stop politicising the virus. He also said WHO regrets the U.S. decision and is reviewing the impact of American funds being withdrawn. WHO, he said, would work with its partners to fill any financial gaps that arise so the “work continues uninterrupted”.
What makes up the virus and how drugs act on it
•Everyday, we hear about the novel coronavirus, how it is easily infecting and transmitting itself from people to people, and how scientists and medical experts are waging a war against its spread. We also hear how different this is from bacteria, and why treating people with antibacterial drugs may not help wipe this out. What then is the difference between a virus and a bacterium? Well, bacteria are alive. Each bacterial cell has its own machinery to reproduce itself. Take a bacterial cell, and put it in a solution containing nutrients, it grows itself and multiplies in millions. The genes in the cells (genome, made up of DNA molecules, the information contained in which is transcribed as a message to the messenger molecules called RNA), and the message therein is translated into action molecules called proteins, which are the foot-soldiers that help the growth and multiplication of the bacterium. Coronaviruses do not have DNA as their genome, but RNA; in other words, they can only translate and not transcribe. Thus, they are ‘dead’, unable to renew and grow themselves; they need help. This they achieve by infecting ‘host cells’ which they bind to, and multiply by the millions. With no host cell to help, a virus is simply a dead storage box.
The polyprotein strategy
•Upon infection, the entire RNA with its 33,000 bases is translated in one shot as a long tape of amino acid sequences. Since this long chain contains several proteins within it, it is called a “polyprotein” sequence. One needs to analyse this long chain, find the relevant proteins, isolate and study what each of them does in helping infection. (Scientists call the polyprotein a ‘single reading frame’, containing several ‘open reading frames’, namely those that contain a start code and end with a stop code, each containing the relevant protein to be expressed by the host cell). This strategy allows the viral genome to be compact, and express the protein when the need arises. This is somewhat like a thrifty individual who keeps his money in a fixed deposit in a bank, and withdraws chosen amounts as the demand arises. For the virus, the demand is to multiply upon infecting the host. No demand, no withdrawal, no infection, no multiplication!
•As the recent review by Yu Chen and colleagues from China in the Journal of Medical Virology points out (https://doi.org/10.1002/jmv.25681), COVID19 has RNA-based genomes and subgenomes in its polyprotein sequence, that code for the spike protein (S), the membrane protein (M), the envelope protein (E), and the nucleocapsidprotein (N, which covers the viral cell nuclear material) - all of which are needed for the architecture of the virus. In addition to these, there are special structural and accessory proteins, called non-structural proteins (NSP), indeed 16 of them, which serve specific purposes for infection and viral multiplication.
How the drugs work
•We thus have a large set of proteins in the virus, against which a number of potential molecules and drugs can be tried to interfere and stop the production of these viral proteins. Indeed, this has been tried to advantage by several recent publications during the last month alone. One of them has attempted to target the translation of the key enzyme RDRp in the virus, whose production was stopped by the drug Remdesavir. Three studies from the US, Germany and China have come up with methods to stop the production of the enzyme (called CL3pro, also called as Mpro) which is needed to make the spike (S protein). And the paper by Yu Chen et al, quoted above lists as many as 16 NSPs in the viral polyprotein, which can be targeted by potential drug molecules. (And Dr PandurangaRao from Boston is quoted as stating that the enzyme nsp12 to be a high-value target).
•It is important in this context to cite the longstanding excellent work being done by an Indian researcher, Thanigaimalai Pillaiyar (what an auspicious name- in homage to the street he was born in the village, he was born in Thiruvannamalai district in Tamilnadu!), who is settled as a medicinal chemist working at the University of Bonn, Germany since 2013. In a paper full of insight, which he published in 2015-16, titled: ‘An overview of SARS-CoV 3CL protease inhibitors: peptidometrics and small molecule chemotherapy’, that appeared in Journal of Medicinal Chemistry, 2016, 59 (6595-6628)(10.1021/acs.jmedchem.5b01461). In this paper, he used the X-ray crystal structure of a related virus TGEV (Transmissible Gastroenteritis Virus), found by 3D modelling a key enzyme of the SARS-CoV, called Chymotrypsin-like Cysteine Protease (3CLpro) also called the main protease (Mpro), and found that this enzyme fits into the virus structure in a lock and key manner. The next step after this molecular modelling was to find drugs that can deactivate this binding and thus inhibit the SARS-CoV from infecting. A total of about 160 known drugs were predicted to be of value with varying efficiency. Recall that this prediction and the drug list was suggested by him before the crystal structure (or the cryo-electron microscopy of COVID-19 was known) 3-4 years later! Pillaiyar and coworkers have updated their findings in their recent paper in January 2020, in the journal Drug Discovery Today (https://doi.org.10.1016/j.drudis.2020.01.015).
•India is well versed with expertise in the area of organic and medicinal chemistry since the last 90 years and in manufacturing quality drug molecules, and exporting them for use at home and across the world since the 1970 patents act of India. Our expertise today, in both the public and private sector, includes not just synthesizing made-to-order molecules, but has added new methods involving computer modeling of target proteins from bacteria and viruses, homology modelling, drug design, repurposing of drugs, and other methods. (It is worth noting that Dr. Pillaiyar has active collaboration for quite some time with Sangeetha Meenakshisundaram at the Srikrishna College of Engineering and Technology, Coimbatore, and Manoj Manickam at the PSG Institute of Technology and Applied Research, also at Coimbatore). The CSIR has taken upon itself the express task of coming out with molecules and methods to counter the dreaded virus, and we have every hope that they will succeed in the nearest future!
📰 Will convalescent plasma help COVID-19 patients?
Why is this strategy that has worked with several other diseases of interest now? And how are trials progressing?
•The story so far: As the months progress, the world seems still maddeningly short of definitive treatment or vaccine options against COVID-19. However, as the number of people with active COVID-19 infections has increased globally, scientists are “close” to deciding on some promising drug and vaccine candidates and clinical trials are on at multiple centres to test the safety and efficacy of these options. Among the many scientific terms that seem to have entered common parlance with COVID-19 is convalescent plasma. While we may be, in an optimistic scenario, a few weeks or months away from drugs or vaccines, clearly some front-runners have emerged, including remdesivir (originally designed to target the Ebola virus) and convalescent plasma. Convalescent plasma is a time-tested strategy that has worked successfully with several other diseases, and doctors struggling to bring relief to COVID-19 patients have turned towards it — it is blood derived from patients who have recovered from COVID-19 — on the assumption that their body contains antibodies it used to fight the virus.
What is convalescent plasma? How does it work?
•As Dr. Michael Joyner, professor, Mayo Clinic, explains on the institution’s website: People who have recovered from COVID-19 have antibodies to the disease in their blood. Doctors call this convalescent plasma. Researchers hope that convalescent plasma can be given to people with severe COVID-19 to boost their ability to fight the virus. The blood — about 800 ml or so — is collected from the donor through the regular withdrawal process, tested for other pathogens, and if safe, the plasma component is extracted and subsequently used for transfusion on to patients. Everyone who has suffered from a disease possibly carries what are called neutralising antibodies that when extracted via plasma and transfused on to others with the infection can help their immune system fight it off. Whether it works or not depends on whether the disease produced a lot of antibodies in people or not, explains Dr. Priya Sampathkumar, infectious diseases consultant and medical director, infection prevention and control, Mayo Clinic, U.S. For some diseases, the body needs more cellular immunity to fight the infection, while for others, the body needs more antibodies. Most diseases, however, require a combination of both these mechanisms, Dr. Sampathkumar points out.
•Since trials are going on, there is no standardised protocol on how much of convalescent plasma or how often it must be used. Even before we knew what sort of antibody levels have to be administered, doctors began using this technique because there did not seem to be anything else that worked. The understanding why some people have more antibodies and some have less, whether those who were asymptomatic have antibodies at all, and in what strength, are issues that will have to be answered over the course of the trials.
•But, she says, these are important questions that need answers, because giving whole plasma to an individual may even overload the system since it might be a large volume. There are no commercially available assays in the market that could measure the antibody level in the plasma. However, research is on at Mayo Clinic for an assay that would take at least a few weeks, to conduct such a test, according to Dr. Sampathkumar. Once that is done, experts would have to figure out the standard minimum dose of antibodies that will kickstart the immune response in the recipient against COVID-19 infection. Rapid serological antibody tests have only recently become available for testing in some nations.
How far are we from using it and what are the challenges?
•Dr. Sampathkumar says for all these studies to get off the ground, researchers would need enough donors who have recovered fully and can be tested for other pathogens as well. People should be willing to donate plasma, and good tests should emerge to estimate how many antibodies they have. While studies are required to show the timing and dosage, there is broad consensus that early administration will be ideal. Dr. Joyner says attempts are on to understand the issue via the large cohort of patients being observed. His colleague, Dr. Sampathkumar, explains, early on in the disease, there is a lot of virus in the system and the antibodies will bind with the virus eliminating it. If this is not done at this stage, then the virus sets off a cascade of inflammation in the body. If the patient has reached that stage, the plasma may not be helpful. And yet, at least two studies from China, the results of which were published in peer-reviewed journals, showed that in severe patients in the intensive care unit, the level of neutralising antibodies increased rapidly or remained high after convalescent plasma transfusion and the clinical symptoms also showed significant amelioration.
•Trials are also required to examine the effect of other anti-virals or anti-inflammatory drugs on convalescent plasma, and see if there is an additive effect or take-away from the benefits, she adds.
•Dr. Joyner speculates that there will likely be concentrated immune globulin products in a few months, and these will likely supersede plasma as a way to deliver passive immunity via antibodies to both patients with active disease and to temporarily prevent disease.
•Since it rests on blood donation, people from the more common blood groups, for instance, O+ve, will have easier access to plasma. Naturally, the pool for rare blood groups is going to be smaller. However, experts have been laying emphasis on the need for people who have recovered to voluntarily come forward and donate plasma to help with research and other patients.
What is the future?
•Trials will conclude in a few weeks/months for definitive conclusions to emerge. The Indian Council of Medical Research has approved Delhi and Kerala to undertake clinical trials, and Tamil Nadu has also applied for permission to conduct trials in the State.
•If trials clear convalescent plasma and approvals are given for a clinical rollout, it can be employed in hospital settings widely to help patients.
•If that were to come to pass, the government would also do well to bring in regulations to ensure that plasma donors are not exploited under any circumstances. Creating a broad-based pool of donors would also be advisable, following the Mayo Clinic model, to cover rare blood types as well.
📰 Govt. nod mandatory for FDI from neighbouring countries
Move may be aimed at preventing ‘opportunistic takeovers’ by Chinese entities
•In a move that will restrict Chinese investments, the Centre has made prior government approval mandatory for foreign direct investments from countries which share a land border with India. Previously, only investments from Pakistan and Bangladesh faced such restrictions.
•The revised FDI policy is aimed at “curbing opportunistic takeovers/acquisitions of Indian companies due to the current COVID-19 pandemic,” said a press release from the Department for Promotion of Industry and Internal Trade on Saturday.
‘With land borders’
•“A non-resident entity can invest in India, subject to the FDI Policy except in those sectors/activities which are prohibited,” says the new policy.
•“However, an entity of a country, which shares land border with India or where the beneficial owner of an investment into India is situated in or is a citizen of any such country, can invest only under the Government route.” Pakistani investors face further restrictions in requiring government approval for FDI in defence, space and atomic energy sectors as well.
•India shares land borders with Pakistan, Afghanistan, China, Nepal, Bhutan, Bangladesh and Myanmar. Investors from countries not covered by the new policy only have to inform the RBI after a transaction rather than asking for prior permission from the relevant government department.
•With many Indian businesses coming to a halt due to the lockdown imposed to contain the COVID-19 pandemic and valuations plummeting, a number of domestic firms may be vulnerable to “opportunistic takeovers or acquisitions” from foreign players. Last week, housing finance company HDFC informed the stock exchanges that the People’s Bank of China now holds a 1.01% stake in the company. This was an instance of portfolio investment through the stock market and not FDI.
•The official statement added that a transfer of ownership of any existing or future FDI in an Indian entity to those in the restricted countries would also need government approval. The decisions will become effective from the date of the Foreign Exchange Management Act notification.
