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Special Issue/June 2020 COVID-19 CRISIS Nature India examines the pandemic The full picture Vaccine race Dangerous ideas In association with Why patient data The most promising Combatting viral matters approaches misinformation
2 | Nature India | Vol 576 | 5 December 2020
30 June 2020
From the editor
EDITORIAL
New Delhi, India
natureindia@nature.com
Editor-in-chief: Subhra Priyadarshini
Editors: Rebecca Dargie, Sara Phillips, Amanda Rider
Art and design: Paula Lock, Marian Karam
Photographic editor: Amany Shawkey Subhra Priyadarshini introduces this special
Project management: Shaimaa Ramadan
Creative director: Wojtek Urbanek COVID-19 issue of Nature India.
F
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Senior Manager, India
Sonia Sharma or most of us, 2020 will be marked as the year of great imponderables. We seem to know
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Sonia.sharma@nature.com as much about the new coronavirus SARS-CoV-2 and its effects on the human body and
societies at large, as we don’t. Ever since the virus broke out, ‘uncertainty’ is one of the
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Across the globe, very few lives have been untouched by the direct or indirect effects
REGISTERED OFFICE of the novel coronavirus. China, the most populous nation on Earth, bore its brunt as the virus
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New Delhi, 110 001 India reacted quickly to contain it, the contagion had spread via international travellers.
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www.natureasia.com/en/nindia India, the world’s second most populous nation, reported the first case of the novel coro-
navirus on 30 January 2020. The number of people becoming infected by the virus began to
© 2020 Springer Nature Limited. All rights reserved. rise quickly, prompting the government to impose a two-month complete shutdown of the
country – the longest ever in its history.
DISCLAIMER An enormous population, a weak healthcare system, and traditionally meagre investments
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of interest to the sponsor, while satisfying the NRG
the severe economic and social fallouts, like elsewhere in the world, forced the government
editorial values and our readers’ expectations. Most of our to allow a regulated easing out of lockdown.
special issues focus on affairs pertaining to science and
research in India and at the same time are of significance
Nature India started reporting on COVID-19 in India from the outset. As the pandemic began
to the global scientific community. unsettling every facet of life from healthcare to education and community life to businesses,
our coverage embraced a new normal, going beyond pure science to a parallel reflection of its
The Nature India Special Issues are available freely for
download at www.nature.com/nindia. links with society, culture and life.
Nature India’s special issue on COVID-19, therefore, seeks to consider answers from the
Connect with us:
facebook.com/npgindia @NatureInd future. In a rapidly evolving pandemic, some of the articles in this special issue bear a time
stamp. However, they will hopefully remain relevant for a long time to come as chronicles of
Cover image: the biggest human crisis any of us has faced in our lifetimes. As we scrutinize India’s response
Ashish Vaishnav/SOPA Images/LightRocket via Getty to the mammoth healthcare challenge, we also look at vaccines and drugs being tested across
Image
the world in a hope to arrest the respiratory infection. We dive into the science of how the
immune system responds to the virus and question whether submitting genome sequences
to global repositories at record speeds makes any sense without accompanying patient data.
We explore how the packaging of the future would look, and explain how to care for the elderly
and critically ill in times when hospitals are struggling to accommodate COVID-19 patients.
Everyone has a COVID-19 story to tell. We feature some extraordinary everyday stories — a
doctor on the frontline handling COVID-19 patients in a Delhi hospital, a scientist in the southern
state of Kerala who hasn’t been able to start her dream laboratory due to the lockdown, and an
Arctic explorer who endured months of darkness and isolation in the north pole before coming
back to a world struck by a new virus.
This special issue also features the story of Ayurveda, and why it is time for India to apply
scientific rigour to the study of the ancient system of medicine. We talk of the importance of
socially influential groups, scientists, and religious leaders, in spreading the right messages
and scotching misinformation in a public health emergency.
In many countries including India, the pandemic is testing the limits of science and of human
perseverance. It is taking a toll on our mental health – how we live, work and communicate are
set to change for a long time to come.
Science will hopefully find a solution to this unprecedented human suffering soon.
Subhra Priyadarshini
Editor-in-chief
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30 June 2020
Contents
A lifeline vaccine must be universal p. 6 Coronavirus sequencing efforts urgently Spreading the word in times of fear p. 34
need patient data. p11
Editorial 22 A call to sow seeds for nutrition 32 Misinformation and myths
security go viral
1 Subhra Priyadarshini introduces
India announced free food grains From the belief that drinking tea
this special COVID-19 issue of
for more than 800 million people will protect against COVID-19, to
Nature India.
during the COVID-19 lockdown. poisonings, misunderstanding and
Features and comments However, nutrition security is hoaxes are common in this time of
more important than food security uncertainty.
4 Indian scientists in vital search during this crisis and beyond,
for solutions 34 Spreading the word in times
experts say.
Finding rapid approaches at all of fear
levels to protect the world’s second 24 Protecting the elderly from the Religious leaders can help
largest population will be crucial. risks of isolation disseminate important messages in
The physical and psychological the COVID-19 crisis.
6 A lifeline vaccine must be health of our senior citizens
universal 36 From deep freeze to a lockdown
demands urgent attention, now
It is time to revamp global supply Polar scientist Vishnu Nandan
more than ever before.
mechanisms to ensure everyone returned home from a four-month
has access to a coronavirus vaccine 26 As COVID-19 takes its toll, burden lockdown in the Arctic. He talked
when it becomes available. of other health crises too heavy to Nature India about coming back
to bear into a world fighting a pandemic.
11 Coronavirus sequencing efforts Doctors struggle to treat those
urgently need patient data 38 For doctors, intensive care takes
with compromised immunity as
Unless each sequence of the virus on a whole new meaning
the pandemic stretches healthcare
in the global open repositories When Viny Kantroo, a respiratory
system capacity.
comes with additional patient diseases specialist, started seeing
information, the practical benefits 28 Packaging the future of industry COVID-19 patients in her Delhi
of such record sequencing are lost. Safe delivery of materials is key to hospital, a grim reality unfolded,
successful resumption of economic professionally and personally.
14 A tug of war in the immune activity.
system 39 Starting a lab in a pandemic
Developing an understanding of 30 Time to bring scientific rigour On the brink of starting her first
the root of SARS-CoV-2 is proving to the complex challenge of laboratory, COVID-19 threw
difficult, despite an urgent and Ayurvedic medicine Poonam Thakur’s lofty plans into
widespread search. A look at traditional approaches disarray.
in the context of the COVID-19
20 Carbon in the time of COVID-19 40 Let COVID-19 expand awareness
pandemic.
Near-real-time data show which of disability tech
sectors, countries and events had The pandemic’s disruption shows
the most impact on slashing carbon how much academia could learn
emissions, but it is unclear how from the disability community.
long the dip will last.
Nature India COVID-19 Special | June 2020 | 3
Feature
INDIAN SCIENTISTS IN
VITAL SEARCH FOR
SOLUTIONS
Finding rapid approaches at all levels to protect the
world’s second largest population will be crucial.
By Vanita Srivastava
I
ndia’s scientists are racing to find interdis- multi-agency empowered committee to speed
ciplinary solutions in the country’s high- up research and development decisions in
stakes fight against the novel coronavirus view of the critical need to increase testing
WE ARE WELL EQUIPPED
pandemic. facilities for COVID-19.
With an unprecedented demographic Scientists at the CSIR- Institute of Genomics
TO TAKE A VACCINE
challenge at hand and struggling with the and Integrative Biology (IGIB) may have found
traditionally limited budgets allocated a solution that can be scaled up. A team led by
to science, the country’s researchers are
working overtime to provide small and big CANDIDATE FROM Souvik Maiti and Debojyoti Chakraborty has
designed a paper strip-based testing assay that
solutions – from predicting statistical trends
and making mathematical models to develop- THE LABORATORY TO can detect the viral RNA of the novel corona-
virus SARS-CoV-2 within an hour, “making any
ing rapid paper-based test kits and low-cost
ventilators.
Some are mass-producing masks and hand
INDUSTRY.” lab with a thermal cycler capable of perform-
ing this test,” Chakraborty said.
The paper-strip test uses CRISPR-Cas9 tech-
sanitisers while others repurpose drugs and nology – the assay works by converting the
ambitiously work towards a vaccine to flatten and entrepreneurs. C-CAMP chief executive, viral RNA into DNA, amplifying it, and deploy-
the curve of the disease. Taslimarif Saiyed said innovators will be able to ing the Cas9 complex to detect any genetic
Soon after Prime Minister Narendra Modi take advantage of an ecosystem of scientists, material from the virus. “It can work with very
announced a nation-wide lockdown (from 25 regulators, investors and industry in “closing low RNA copies in the sample. The kit would
March 2020), India’s Department of Science last-mile gaps in commercializing their tech- cost less than 500 rupees,” Chakraborty said.
and Technology (DST) set up a COVID-19 Task nologies”. IGIB director Anurag Agrawal said the
Force to hunt for leads in its R&D labs, aca- Faced with the public health emergency, institute was also developing a ‘sample to
demic institutions, start-ups and small enter- a group of scientists urged the government sequence’ strategy, where test samples can
prises. Of the 200 proposals this task force to devise measures that can bolster corona- be diagnosed by next generation sequencing
received, DST identified 20 for swift funding virus-related research in India. “During this (NGS). This could help surveillance efforts to
to scale up promising products in diagnostics, lockdown, we request the government to keep track the spread of the virus.
drugs, ventilators and protection gear. those research laboratories operational which “Sequencing can strengthen genomic epi-
“We mapped their supply along with that of are working on finding a cure for the disease,” demiology, genetic variants linked with vir-
breathing aids, disinfectant systems, rapid inex- the scientists said in a joint statement on 31 ulence, evolution and transmission pattern,”
pensive diagnostics and monitoring technol- March 2020. “Many scientists are attempting said Rajesh Pandey, who is leading this genom-
ogies, and will try to match the demand,” DST to create social awareness about the disease. ics effort. His team is using a combination of
secretary Ashutosh Sharma told Nature India. We urge the government to take advantage of sequencing platforms to meet the dual tar-
In Bengaluru, the Department of Biotech- the resources and expertise available within get of scale and sensitivity for any India-spe-
nology’s bioincubator Centre for Cellular and the scientific community.” cific strain. “It is important to ascertain the
Molecular Platforms (C-CAMP) quickly cata- genomic sequence of strain(s) prevalent in
pulted a technology accelerator in partner- Rapid testing India vis-a-vis other geographical locations
ship with the United Nations Health Innovation India has been criticized for its poor mass and symptom spectrum. This information
Exchange (UNHIE) and the non-profit firm, testing capability owing to a shortage of test- would be important to correlate specific
Social Alpha, to help innovators, start-ups ing kits. The government has now created a strains with virulence or aggressive nature of
4 | Nature India COVID-19 Special | June 2020
develop an antibody-based therapy,” said
NII director Amulya Panda. Studies are also
underway on the spike protein of the novel
coronavirus to develop a vaccine. “We have
previously developed an immunomodula-
tor for leprosy and are well equipped to take
a vaccine candidate from the laboratory to
industry,” he said.
Private enterprise
Beyond the action in government laborato-
ries, technologists are devising interesting
ways to stop the spread of the virus. One
such government-led effort is the ‘Corona
Kavach’ app that can alert users when they
come in proximity of a confirmed coronavirus
positive person. Many state governments,
including Maharashtra, Goa, Karnataka, Tamil
TAUSEEF MUSTAFA/AFP VIA GETTY IMAGES
Nadu and Kerala, have launched similar track-
ing apps.
Another team of researchers at the Indian
Institute of Technology Delhi has developed
an app that alerts the user to a population sus-
pected to be infected.
“The app uses bluetooth technology to
identify people who may have come within the
range of two metres around a coronavirus-in-
A patient in Kashmir has his temperature tested. fected patient,” said Vikas Upadhyay the lead
researcher of the team. The secure server data
the virus, and tailor-make contingency plans drug development through public-private can be analysed to identify, trace and monitor
for India,” he said. partnership, creating biomarkers for disease social distancing norms.
Pandey and colleagues are developing severity,” Basu said. Private players are also chipping in to
sequencing strategies, combining the num- Epidemiology research should take cen- provide testing solutions. A Pune-based
ber and length of sequences, for mass bar- tre stage, said clinician-scientist Gagandeep molecular diagnostics company Mylab Dis-
code-based screening. “It’s a multi-pronged Kang. That would help understand where the covery Solutions developed the first COVID-
sequencing strategy, which in conjunction disease has spread and to what extent. Kang, 19 testing kit in India and is producing about
with other epidemiological data, would help who is the executive director of the Transla- 200 kits a day, each kit capable of testing
public health authorities manage the outbreak tional Health Science and Technology Institute 100 samples.
and design potential regions or targets for (THSTI) in Faridabad, said that her institution “We are delivering these kits to govern-
screening,” Pandey said. is working on an ELISA test for serological stud- ment- authorized labs,” said Gautam Wank-
ies across the country which will essentially hede, Mylab’s director for medical affairs.
Taming the virus help understand how much the disease has The kit can give test results within 2.5 hours.
Another group of virologists at the National spread in India. The company’s executive director, Rahul
Institute of Virology in Pune is focusing its “The Indian population is dense and there Patil said in emergency conditions, they can
energies on how the virus interacts with its are so many poor people,” she said. Social dis- ramp up production to enable 50,000 tests
host by imaging virus infected host cells with tancing, therefore, may be a difficult proposi- a day.
ultrastructural tools. NIV Deputy Director tion. The first task should be boosting public NovaLead Pharma, another company from
Atanu Basu told Nature India that they are also health research to help control the spread. The Pune in Maharashtra, the state with the highest
trying to identify key cellular sites of replica- next step should be research for developing number of novel coronavirus infected people
tion, virus morphogenesis and development. additional diagnostic tools, drugs and vac- in India, has deployed computational tech-
“This will give us better knowledge to supple- cines, Kang said. nology for identifying existing drugs poten-
ment studies by drug development groups,” “We are also working on rapid diagnostic tially effective against the SARS-Cov2 virus as
Basu said. tests,” she said. well as for minimizing its impact on the human
Basu’s team was the first to image the novel The Indian Council of Medical Research body.
coronavirus from an Indian patient using a (ICMR) maintains that India will soon start Through a complex and extensive compu-
transmission electron microscope. “Native manufacturing serological testing kits. “We tational study involving 2010 approved drugs
images in clinical material can be very use- are hopeful that India will be able to develop and 30 potential viral and human targets,
ful for pathogenesis studies,” he said. NIV is at least one serological diagnostic testing tool NovaLead has identified 42 existing drugs
looking to collaborate with structural biology in the next few months,” the council’s chief epi- which may be helpful to patients at different
groups and to pool resources, especially in the demiologist and communicable disease expert stages of SARS-Cov-2 infection. “Use of exist-
area of cryoelectron microscopy, to study the R R Gangakhedkar told Nature India. ing drugs already approved by the regulators
replication and organization of this virus in Delhi-based National Institute of Immunol- can offer a huge relief in the short to medium
depth. “We should prioritize development ogy (NII) is procuring viral samples and blood term, if found effective against Covid 19,”
of in-vitro and in-vivo animal models for bio- from recovered patients. “We will analyse the said NovaLead managing director Supreet
assays. Besides, we should aim at antiviral antibody quality in the blood with an aim to Deshpande.
Nature India COVID-19 Special | June 2020 | 5
Comment
A lifeline vaccine must be universal
Arun Kumar and Tung Thanh Le
It is time to revamp global supply mechanisms to ensure everyone has access
to a coronavirus vaccine when it becomes available.
© UNIVERSITY OF QUEENSLAND
When a safe and effective vaccine against COVID-19 is licensed for use, there will be a global clamour for access to supplies.
6 | Nature India COVID-19 Special | June 2020
T
he COVID-19 pandemic has triggered CEPI is now facilitating the development development, regulatory review, and manu-
more than 115 vaccine projects around of nine COVID-19 vaccines, including those facturing — each step can take several years.
the world. by Moderna, CureVac, Inovio, the University Some novel platform technologies and
After the Ebola outbreak of 2014 in of Oxford, Insitut Pasteur/Themis Biosciences, approaches are reducing these long timelines,
West Africa, international research Novavax, the University of Hong Kong, and could provide a universal framework for
bodies and governments, including of the University of Queensland, and Clo- vaccine design, manufacturing and analytical
India and Norway, the Bill and Melinda Gates ver Biopharmaceuticals, across six plat- protocols for known and unknown pathogens.
Foundation, the Wellcome Trust, and the World form technologies. At the time of writing, When these standardized and validated pro-
Economic Forum, joined forces in the search three candidates have started phase I cesses are applied across multiple vaccine
for new vaccines and formed The Coalition clinical trials. targets, they could help with accelerating
for Epidemic Preparedness Innovations Vaccine development demands explor- animal and clinical testing, engagement of
(CEPI). atory and preclinical research, clinical critical partners and license processes across
jurisdictions. Implementation of several steps
in parallel, could also accelerate the vaccine
development process.
DNA and RNA vaccines
Vaccines based on genetic instructions
(through DNA or RNA) offer advantages over
traditional approaches because of speed, ease
of antigen design, and a generic manufactur-
ing process. These vaccines avoid the use of
cell culture, are fully synthetic, and can be
directly delivered into the cells where protein
synthesis takes place.
“Implementation of
several steps in parallel
could accelerate vaccine
development.”
Messenger RNA (mRNA) vaccines (consist-
ing of RNA strands coding the antigenic part
of the pathogen) are very attractive because
of the short-half life and direct delivery of anti-
gen-encoded sequence into the cytoplasm. A
chemically modified mRNA vaccine (mRNA-
1273) against SARS-CoV-2 has been developed
by Moderna and has started a phase I trial. The
previous phase I trial based on this technology
induced robust immune responses. Demon-
strating the speed of this platform, just after
sequence identification, Moderna started the
vaccine development process and within 63
days initiated a phase I trial.
Another mRNA-based COVID-19 vaccine
candidate in pre-clinical stages is being devel-
oped by CureVac, a company based in Tubin-
gen, Germany. CureVac’s technology uses
naturally occurring nucleotides and recently
has shown that the one microgram formula-
tion of its Rabies mRNA vaccine can induce a
strong immune response in humans.
Additionally, CureVac is in the process of
developing a fully automated proprietary
mobile manufacturing platform, the RNA
Printer, which may further enhance speed
and help with rapid responses to the out-
break globally. Very recently, BioNTech in
partnership with Pfizer started phase I/II
clinical trials for a COVID-19 vaccine, BNT162.
Other advanced vaccine development
Continued on page 10
Nature India COVID-19 Special | June 2020 | 7
Infographic
THE RACE FOR AN ARRAY OF VACCINES
CORONAVIRUS
All vaccines aim to expose the body to an antigen that won’t
cause disease, but will provoke an immune response that can
block or kill the virus if a person becomes infected. There are
at least eight types being tried against the coronavirus,
and they rely on different viruses or viral parts.
Virus Viral vector
VACCINES
Inactivated Replicating
Weakened Non-replicating
Nucleic acid Protein-based
DNA Protein subunit
By Ewen Callaway; RNA Virus-like particles
design by Nik Spencer.
Virus
Multiple vaccines are being developed against SARS-CoV-2 by Viral vector
research teams in companies and universities across the world. Nucleic acid
Researchers are trialling different technologies, some of which Protein-based
haven’t been used in a licensed vaccine before. At least six groups Other*
have already begun injecting formulations into volunteers in safety 0 5 10 15 20 25 30 35
trials; others have started testing in animals. Nature’s graphical Number of vaccines in development
guide explains each vaccine design. * Other efforts include testing whether existing vaccines against poliovirus or
tuberculosis could help to fight SARS-CoV-2 by eliciting a general immune
response (rather than specific adaptive immunity), or whether certain
immune cells could be genetically modified to target the virus.
VACCINE BASICS: HOW WE DEVELOP IMMUNITY
The body’s adaptive immune system can learn to recognize new,
invading pathogens, such as the coronavirus SARS-CoV-2. VIRUS VACCINES
At least seven teams are developing vaccines using the
virus itself, in a weakened or inactivated form. Many existing
Coronavirus infection* vaccines are made in this way, such as those against
Spike protein The virus uses its surface spike protein to lock measles and polio, but they require extensive safety testing.
onto ACE2 receptors on the surface of human Sinovac Biotech in Beijing has started to test an
M protein cells. Once inside, these cells translate the inactivated version of SARS-CoV-2 in humans.
virus’s RNA to produce more viruses.
RNA Weakened virus Inactivated virus
A virus is conventionally weakened In these vaccines,
for a vaccine by being passed the virus is rendered
through animal or human cells uninfectious using
1. Virus enters until it picks up mutations that chemicals, such as
the body make it less able to cause disease. formaldehyde, or heat.
Body Codagenix in Farmingdale, Making them, however,
New York, is working with the requires starting with
Serum Institute of India, a vaccine large quantities of
ACE2 receptor manufacturer in Pune, to weaken infectious virus.
Human cell SARS-CoV-2 by altering its genetic
2. Virus enters
code so that viral proteins are
4. Virus assembly a cell
produced less efficiently.
Viral RNA translated
into proteins Vesicle
5. Virus 3. Virus fuses with vesicle
release and its RNA is released
Immune response*
Viral
Specialized ‘antigen-presenting cells’ engulf the virus
peptide
and display portions of it to activate T-helper cells.
Virus ingested
by antigen- T-helper cells enable other immune responses: B cells
presenting make antibodies that can block the virus from infecting
cell (APC) cells, as well as mark the virus for destruction. Cytotoxic Body
T cells identify and destroy virus-infected cells.
Vaccine
B cell Anti-coronavirus
antibody Cell
T-helper cell
Long-lived ‘memory’ Virus
Cell replicates
destroyed B and T cells that
recognize the virus
Cytotoxic can patrol the body
T cell for months or years,
*Simplified providing immunity
8 | Nature India COVID-19 Special | June 2020A process called
electroporation Nucleus
creates pores in
membranes to mRNA
increase uptake
of DNA into a cell Viral
proteins
Cell
NUCLEIC-ACID VACCINES Electroporation
At least 20 teams are aiming to use
genetic instructions (in the form of
DNA or RNA) for a coronavirus Coronavirus
protein that prompts an immune peptide
response. The nucleic acid is
inserted into human cells, which DNA
DNA
then churn out copies of the virus vaccine
protein; most of these vaccines
encode the virus’s spike protein. Coronavirus
Body
spike gene
RNA- and DNA-based vaccines are Immune response
safe and easy to develop: to
produce them involves making
RNA RNA is often
genetic material only, not the
virus. But they are unproven: vaccine encased in a
no licensed vaccines use this lipid coat so it
technology. can enter cells
RNA
VIRAL-VECTOR VACCINES PROTEIN-BASED VACCINES
Around 25 groups say they are working on viral-vector vaccines. A virus such as Many researchers want to inject coronavirus
measles or adenovirus is genetically engineered so that it can produce proteins directly into the body. Fragments of
coronavirus proteins in the body. These viruses are weakened so they cannot proteins or protein shells that mimic the
cause disease. There are two types: those that can still replicate within cells and coronavirus’s outer coat can also be used.
those that cannot because key genes have been disabled.
Replicating viral vector Non-replicating viral Protein subunits
(such as weakened measles) vector (such as adenovirus) Twenty-eight teams are working on vaccines with viral
The newly approved Ebola vaccine is an No licensed vaccines use this protein subunits — most of them are focusing on the virus’s
example of a viral-vector vaccine that method, but they have a long spike protein or a key part of it called the receptor binding
replicates within cells. Such vaccines history in gene therapy. Booster domain. Similar vaccines against the SARS virus protected
tend to be safe and provoke a strong shots can be needed to induce monkeys against infection but haven’t been tested in people.
immune response. Existing immunity to long-lasting immunity. US-based To work, these vaccines might require adjuvants —
the vector could blunt the vaccine’s drug giant Johnson & Johnson is immune-stimulating molecules delivered alongside the
effectiveness, however. working on this approach. vaccine — as well as multiple doses.
Coronavirus
spike gene
Virus-like particles
Coronavirus
CHART SOURCES: NATURE ANALYSIS BASED ON WHO COVID-19 VACCINE LANDSCAPE/MILKEN INSTITUTE COVID-19
Empty virus shells mimic the coronavirus
Viral genes spike gene
TREATMENT AND VACCINE TRACKER/T. THANH LE ET AL. NATURE REV. DRUG. DISC. HTTP://DOI.ORG/GGRNBR
structure, but aren’t infectious because
(2020)/F. AMANAT & F. KRAMMER IMMUNITY 52, 583–589 (2020)/W. SHANG ET AL. NPJ VACCINES 5, 18 (2020)
Viral genes they lack genetic material. Five teams
(some inactive) are working on ‘virus-like particle’ (VLP)
vaccines, which can trigger a strong
immune response, but can be difficult
to manufacture.
Spike
protein FIRST PUBLISHED IN NATURE VOL 580, PAGE 576 (2020) (C) SPRINGERNATURE 2020
M protein
Virus Antigen-
replicates presenting
cell
VLP
Coronavirus
peptide
First published in Nature 581, 9 (2020)
(©SpringerNature 2020).
Immune response
Nature India COVID-19 Special | June 2020 | 9Comment
candidate based on RNA technology, vaccine (NVX-CoV2373) based on proprietary SARS-CoV-2 sequence. CEPI just announced
including Imperial College London, Tongji recombinant nanoparticle technology. The a partnership with the Clover Pharmaceuti-
University/Chinese Centre for Disease NVX-CoV2373 vaccine is designed to make a cals for development of a SARS-CoV-2 spike
Control and Prevention and Translate stable form of prefusion form of spike protein. (S)-protein subunit vaccine candidate based
Bio/Sanofi, are also progressing with impres- Immunization of NVX-CoV2373 in animals on innovative Trimer-Tag© technology. Vax-
sive speed. showed strong immunogenicity. Novavax ine, SK Bioscience and G+Flas Life Science
Inovio’s DNA vaccine (INO-4800) against is expecting to start phase I clinical trial in are also working towards development of
COVID-19, initiated phase I trials within mid-May (within 125 days after sequence COVID-19 vaccines based on the recombi-
86 days. Scientists at Inovio started to design identification). This platform has the potential nant approach.
and synthesize a DNA vaccine, which con- to rapidly generate and manufacture vaccine When combined with recombinant pro-
sists of a DNA plasmid containing genes candidates within 90 days (from the identifi- tein-based vaccines, adjuvants (substances
encoding for the SARS-CoV-2 spike pro- cation of gene sequence), as seen in an influ- that modulate and enhance immune response
tein. This vaccine can be given through enza A/Anhui/1/2013 (H7N9) and Ebola vaccine when combined with antigen) can help in
the skin with the help of a next-generation candidates. Medicago is another advance VLP boosting stronger and long-lasting immunity.
electroporation device, which allows candidate with ready material for pre-clinical Furthermore, adjuvants also reduce the dose
smooth entry of DNA into the human cells studies. required, allowing more vaccine doses to be
with the help of an electric current. In made available, which is especially impor-
previous preclinical and clinical studies, Traditional methods and adjuvants tant in a pandemic. GlaxoSmithKline, Seqi-
Inovio’s platform technology induced robust Traditional methods such as inactivated rus and Dynavax have committed to making
T-cell and antibody responses. Zydus Cadila and live attenuated approaches are among innovative licenced adjuvants (ASo3, MF59
has recently been recommended for funding the most advanced candidates for COVID-19 and CpG 1018), respectively) available to
support from India’s Department of Biotech- vaccines. Recently, an inactivated vaccine partners supported by CEPI to enhance the
nology (DBT) for advancing its DNA-based developed by Sinovac commenced a phase I development of effective vaccines against
COVID-19 vaccine. trial, meanwhile, Wuhan Institute of Biolog- SARS-CoV-2.
ical Product’s vaccine began a phase II trial.
Vaccines based on viral vectors Indian vaccine developer Bharat Biotech along Vaccines for all
Viral-vectors being exploited for gene deliv- with the University of Wisconsin has started Both novel and traditional approaches to
ery and vaccines based on this approach offer development of a COVID-19 vaccine based COVID-19 vaccine development offer differ-
a high level of protein expression, extended on self-limiting version of influenza virus, ent value propositions in relation to speed of
stability and provoke strong humoral (anti- CoroFlu. development and scale of manufacture over
body-mediated) and cellular (T-cell mediated) short and long terms. CEPI has a diverse port-
immune responses. Antigens of interest can “Fair allocation of vaccines folio of candidates based on a wide range of
be expressed efficiently. China’s CanSino vaccine technologies — including novel plat-
Biologics with its recombinant COVID-19
must be urgently and form technologies and other more estab-
vaccine based on Adenovirus Type-5 vector collectively addressed.” lished approaches — to maximize its chances
(Ad5), has moved into a phase II trial. The Uni- of success.
versity of Oxford started the development of a Currently, there is no global entity respon-
COVID-19 vaccine based on a replication Scientists at the University of Hong Kong sible for financing or ordering vaccine manu-
deficient ChAdOx1 platform (chimpanzee (HKU) developed a novel rapid response facture, nor is there a globally fair allocation
adenovirus vector) and began phase I/II clin- technology based on live attenuated influ- system for any vaccines produced. It will be
ical trials on 23 April 2020. The Serum Insti- enza vaccine platform, DelNS1 LAIV. The vital that such a system is in place to ensure
tute of India partnered with the University non-structural protein 1 (NS1) element, which that everyone that no one is left behind. In
of Oxford and was slated to start production makes the flu virus strongly immunogenic and response, the WHO and global leaders from
of vaccine within 2-3 weeks. Additionally, less virulent, was deleted in DelNS1 LAIV. around the world launched the Access to
AstraZeneca will also team up with Oxford Their COVID-19 vaccine candidate was devel- COVID-19 Tool (ACT) accelerator, of which
for mass production of the COVID-19 vac- oped by incorporating the receptor binding CEPI is a founding member, to speed up devel-
cine. Several clinical trials have proved that domain (RBD) of SARS-CoV-2 into DelNS1 opment, production and access to vaccines
it induces immunity and is safe to use against LAIV on its surface. Use of RBD domain and therapeutics.
a range of pathogens. Another CEPI funded only may avoid induction of antibody depend- Globally fair allocation of vaccines is a chal-
consortium led by the Institut Pasteur, Themis ent enhancement of disease. This vaccine lenge that must be urgently and collectively
Biosciences and University of Pittsburgh could prevent both SARS-CoV-2 and influ- addressed by governments, global health
is developing a COVID-19 vaccine based on enza infections and can be administered by leaders, and regulators, while the race for a
the Measles vector. The low cost of manu- nasal route. A phase I trial is expected to start COVID-19 vaccine picks up pace.
facturing and production of large quantities in July.
in less time makes viral vectored vaccines The University of Queensland (UQ) has
favourable for use in low-income and mid- developed molecular clamp technology
dle-income settings. that keeps the spike protein of SARS-CoV-2 in
stable form, which allows the immune sys-
New platforms tem to be able to recognize it. Influenza,
Recombinant nanoparticles are non-infectious Nipah, and MERS coronavirus are some of the
particles and mimic conformational and struc- vaccine candidates that are currently under
tural properties of the native virus but lack development based on this rapid response
genetic material. These properties make them platform technology. Scientists at UQ were *The authors are from the Coalition for
a potential platform technology for vaccine able to generate the COVID-19 vaccine can- Epidemic Preparedness Innovations (CEPI),
development. Novavax developed a COVID-19 didate within 21 days after publication of Oslo, Norway.
10 | Nature India COVID-19 Special | June 2020Feature
© CSIRO
R
A single-stranded RNA virus.
CORONAVIRUS
esearchers mapping the genetic
blueprint of the novel corona-
virus SARS-CoV-2 have by now
SEQUENCING
shared more than 55,000 genome
sequences from across the world
on the open platform Global Initi-
ative on Sharing All Influenza Data
(GISAID). The repository has seen
EFFORTS URGENTLY
unprecedented activity since December when
the first sequence from Wuhan in China came
in. On NCBI’s GenBank, more than 20,000
nucleotide and protein sequences of the virus
have already been submitted.
NEED PATIENT DATA
The virus is set to become the most
sequenced ever.
Researchers, however, warn that unless the
sequences are accompanied by de-identified
data from patients, the billions of dollars
being spent in sequencing the virus globally
will not be of much clinical or epidemiological
Unless each sequence of the virus in the global value, a crucial need during a rapidly evolving
open repositories comes with additional patient pandemic.
Laboratories, clinicians, epidemiologists
information, the practical benefits of such record and governments wanting to quickly use this
sequencing are lost. By Subhra Priyadarshini gold mine of information are meeting a stum-
bling block as they look for more granular data
that should ideally supplement the primary
sequence data.
Nature India COVID-19 Special | June 2020 | 11Feature
“We badly need de-identified meta-data the viral genome. The Central Drug Research team recently analysed the genome sequence
from the patients from whom these sequences Institute (CDRI), Lucknow and IICB, Kolkata are from a COVID-19 patient from Gujarat, agrees.
came so that it makes sense for any kind of also gearing up to sequence the viral genome. “This remains a concern for most of us – to
analysis,” says Seshadri Vasan, who leads the With the 1,000-genome project, about 10 correlate this data with our analysis,” she
Dangerous Pathogens team at the Austral- more facilities across the country will be pulled told Nature India. “It is extremely important
ian Animal Health Laboratory and is senior in to sequence the virus. for us when we want to assign clinical signif-
principal research consultant for Health and Virologist Mitali Mukerji, a genomic scien- icance to our sequencing efforts,” she says.
Biosecurity at the Commonwealth Scientific tist at IGIB who is coordinating CSIR’s sequenc- The reason this additional data is needed
and Industrial Research Organization (CSIRO), ing efforts says at the moment scientists are is that the same viral strain could be fatal for
Australia’s national science agency. only trying to analyse the strain of the virus one person, and result in mild, moderate or
De-identified data does not reveal the iden- and where the sequences came from. “Clini- severe symptoms in others. “And some strains
tity of the patient. Vasan says the minimum set cal history is not getting submitted from any could also be more or less virulent than oth-
of de-identified data that researchers need is place. It’s very important since this is not the ers,” Vasan adds.
the patient’s age, gender, if they had a mild, end of the outbreak,” she says. Epidemiologists Vasan, says the World Health Organization
moderate or severe form of the disease and if need to identity people who might be more at should lead this effort to standardize the
they survived. Questions around lifestyle and risk and analysing clinical information will be meta-dataset that can be followed globally,
comorbidities, such as whether they smoke, crucial, she says. with consistent definitions to categorize sever-
have a pre-existing respiratory illness or diabe- IGIB director and clinician scientist Anurag ity and outcomes of COVID-19. “No country can
tes, are also important to add meaning to this Agrawal, who is overseeing a molecular and solve this problem in isolation. It is important
data. “We usually get information on country digital surveillance project around the for the WHO to specify the minimal meta-da-
and city, but it may be beneficial to have post- genome sequences from India, says it would taset not just for SARS-CoV-2 but also a future
code and ethnicity data too,” he says. be extremely useful to know the viral loads ‘Disease X’,” he told Nature India.
India has announced an ambitious and numbers of symptomatic versus asymp- In the absence of patient meta-data “we
1,000-genome sequencing project to better tomatic cases. “Nothing is meaningful for don’t know how the disease is progressing,
understand the viral and host genomics of molecular epidemiology or our knowledge how long the virus shedding occurs in differ-
the COVID-19 outbreak. India’s Council for of clusters unless these clinical parameters ent settings and what kind of immunity levels
Scientific and Industrial Research (CSIR), are well defined in the data,” he says. exist in individuals or populations,” says epi-
which undertook a 1,008-human genome The biggest barrier, he says, is coordination demiologist Giridhara R Babu from the Public
sequencing project last year, has been leading among researchers sequencing the data and Health Foundation of India (PHFI).
the sequencing efforts in India. agencies uploading it on to the databases. “We have to be very careful in improv-
Scientists at the Centre for Cellular and “We work with the National Centre for Dis- ing the quality of the meta-data and, more
Molecular Biology (CCMB), Hyderabad; the ease Control (NCDC), who have the underly- importantly, have it unbiasedly assessed by
Institute of Genomics and Integrated Biology ing patient information and since they upload people who don’t run the clinical trials,” Babu
(IGIB), Delhi; the Institute of Microbial Tech- the sequences, they do add much more value told Nature India. That way measurement
nology, Chandgarh; the National Institute of to the data.” errors and selection biases can be removed
Virology, Pune, and the Gujarat Biotechnology Upasana Ray, a virologist at the CSIR-Indian from the data to make it more useful.
Research Centre, Gandhinagar are sequencing Institute of Chemical Biology (IICB) whose Information on the severity of symptoms
UNDERSTANDING GENOME SEQUENCES
TRANSBOUNDARY AND EMERGING DISEASES JOURNAL
12 | Nature India COVID-19 Special | June 2020between these data points helps researchers
find out about the different strains of the virus
– including where they came from and how
they continue to evolve,” he says.
Vasan, whose team has analysed the first 181
published genome sequences from the cur-
rent COVID-19 outbreak says the RNA virus
can “evolve into a number of distinct clusters
that share mutations.” The analysis has already
helped determine which strains of the virus are
suitable for testing vaccines underway at the
Australian Centre for Disease Preparedness in
Geelong, Victoria.
RNA viruses, Vasan adds, generally evolve
into clusters and show ‘quasispecies diver-
sity’, meaning not just a single genotype but
an ensemble of related sequences. Quasis-
pecies arise from rapid genomic evolution
powered by the high mutation rate of RNA
viral replication. The novel coronavirus, an
RNA virus, emerged from China and restric-
tions on air travel and movements of people
did not come into place for a while after the
outbreak in Wuhan. “Therefore, the clusters do
not correspond to countries. For instance, the
first 181 published genomic sequences could
be grouped into three clusters (with three
more emerging), and Australian isolates can
be found in each of them,” he says.
For this reason it is unhelpful to call the virus
© CSIRO
‘an Indian strain’ or ‘Australian strain’ or ‘Chi-
nese strain’ or make claims that one regional
Transmission electron microscope image of SARS-CoV-2. strain is more virulent than the other.
“Over time, we may likely find clusters with
and disease progression dynamics would be varied virulence in all countries. The real ques-
immensely helpful when combined with the tion is whether we can link the accumulated
genomic sequences. “For instance, one could mutations in the genome to clinical meta-data
WE MAY FIND CLUSTERS
actually know if there is a sub-group of asymp- and find clinically/epidemiologically meaning-
tomatic people who never go on to develop ful correlations,” he says.
WITH VARIED VIRULENCE
the disease. They would be way more useful A GISAID statement says the circulating
to design a disease modifying mechanism or virus strains globally can be classified into
immunomodulation, instead of the quest for
a vaccine as the endgame.”
Disregarding all these data elements
IN ALL COUNTRIES.” different number of clades based on genetic
variation. ”These are part of the natural evo-
lution of the virus currently not known to be
eliminates the possibility of other non-phar- associated with any differences in virulence,”
macological interventions to disrupt the trans- determine clinical or epidemiological impacts it says. Data from the early outbreak period
mission of the virus, Babu says. of these minor mutations without the under- is not enough for a detailed interpretation of
lying meta-data. Only 14 out of these 388 the early history of global transmissions from
Evolution, mutations and clades sequences had clinical annotations, the rest a few genomes, according to GISAID.
The global effort to peer into the genetic were either annotated as unknown or not at all. Ray, whose team reported in a preprint
make-up of the pandemic-causing virus since CSIRO has developed a novel visualiza- paper two novel mutations in the spike pro-
the start of the COVID-19 outbreak has pro- tion platform — similar to the one used to tein of the SARS-CoV-2 isolate from Gujarat as
vided real-time understanding of the organ- analyse the human genome — to pinpoint dif- compared with the Wuhan virus isolates, says
ism. Databases such as the GenBank and ferences among the thousands of individual these mutations have a somewhat different
GISAID provide ammunition to researchers genetic sequences of COVID-19 now globally origin. “One of the mutations is exclusive in
trying to understand the evolution and muta- available. The data visualization platform the virus obtained from Gujarat whereas the
tions of viruses. They are also solid tools for highlights evolving genetic mutations of the other was also seen in North American and
the research and development of drugs and virus as it continues to change and adapt to European isolates.”
vaccines against the virus. new environments. To date, almost 95% of the strains reported
The data so far reveals some minor muta- “Analysing global data on the published in global databases are from Wuhan in China
tions in the virus which may have no functional genome sequences of this novel corona virus where the outbreak began. “The remaining
consequence, Vasan says. “For instance, when will help fast track our understanding of this 5% are from the rest of the world. So some
we looked at 388 sequences from Australia, complex disease, how changes in the virus descriptions of virulence being low or high
only 162 had protein-changing mutations,” could affect its behaviour and impact,” Vasan in a particular region are wishful thinking at
he says. However, his team was unable to says. “Assessing the evolutionary distance best,” Giridhara Babu says.
Nature India COVID-19 Special | June 2020 | 13Comment
A tug of war in the immune system
Lakshmy Ramakrishnan
Developing an understanding of the root of SARS-CoV-2 is proving
complicated, despite its urgency.
T
he emergence of new pathogens in and 2012. Many bodies have been calling for elucidated three stages of the SARS-CoV-2
humans, that originated in animals, has a ban on wildlife trade ever since infection cycle: the asymptomatic stage with
been a disturbing trend. Disruption in detectable or undetectable viral loads, non-se-
wildlife habitat and changes in human Dangerous liaisons vere symptomatic stage with detectable viral
behaviour are significant contributors Viruses are thrifty organisms; they possess load, and severe disease with high viral load.
to pathogens crossing the species barrier, with only two major biological molecules, protein Onset of symptoms takes place five to six days
globalization an accelerant. Disease-causing and nucleic acids, and yet can do enormous after infection, but studies have reported incu-
microorganisms, that once infected only ani- harm. The proteins carry out the processes bation periods varying from 14-30 days in
mals, have enhanced their infective repertoire of infecting cells and diverting the cell’s some individuals. Symptoms range from mild
to accommodate humans. resources to its own requirements, while the fever, sore throat, cough, myalgia, fatigue,
The 2019 SARS-CoV-2 outbreak is reported genetic material replicates, producing more lymphocytopenia and radiographic signs of
to have originated in a wet animal market, virus particles. SARS-CoV-2 possesses a large pneumonia. Mild cold and flu-like symptoms,
reliant on poaching and the trafficking and RNA genome, which shares significant simi- along with reports of afebrile cases, had ini-
trade of wildlife. The demand for wild ani- larity with that of SARS-CoV. This explains the tially pointed at a broader spectrum of caus-
mals, which are used as exotic foods and in similarity between the two viruses in infection ative agents, such as dengue infection. This in
traditional forms of medicine spurs trade in pattern and their disease outcome in humans. turn, had delayed diagnoses in the early days
wildlife. Within these markets live animals and of the pandemic. However, when the severe
humans come in close contact. Such situations “Scientists and clinicians disease stage emerged, the fine line between
can create a breeding ground for zoonotic ‘flu-like’ and severe became unclear. Severe
viruses to jump from animals to humans
have elucidated three stages disease can lead to shock, acute respiratory
through mutations. of the infection cycle.” distress syndrome, acute cardiac injury, acute
The consensus among scientists is that kidney injury, and death.
SARS-CoV-2 was transmitted from bats to
humans, with pangolins acting as the link. This Transmission of SARS-CoV-2 from humans Fighting back
however is not a simple process. Coronavi- to humans is through direct contact or Infected people recover when their immune
ruses interchange between cycles of active through respiratory droplets transmitted system elicits a directed and durable response
virus production and inactive quiescence from infected individuals. SARS-CoV-2 enters during the first two stages of SARS-CoV-2 infec-
during persistent virus infections in bats. The into the respiratory tract and lungs through tion. It is hypothesized that this protective
latter acts as a means to avoid detection by the the mucosal membranes of the nasal passage anti-viral immunity mainly occurs under the
bat immune system, whilst the former trig- and larynx. It is not yet clear whether it can be setting of overall good health, in the absence
gers immune responses against the virus. Such transmitted through the oral-faecal route, and of underlying diseases, and in the presence of
responses include the production of reactive uncertainty remains over its infectious poten- an appropriate genetic background.
oxygen species, such as superoxide and hydro- tial on inanimate objects. SARS-CoV-2 infection results in severe dis-
gen peroxide, which, in turn induce mutations ease and fatality when there is an imbalance
in the SARS-CoV-2 genome. This virus-host Target practice in the immune response: a tug of war between
interaction generates quasi-species pools of Viruses possess specific proteins, such as the a protective immune response and a dysreg-
virus, with adaptive potential, including the spike protein in the case of SARS-CoV-2, that ulated inflammatory response ensues. The
ability to infect humans. recognize and target specific types of host former induces protective anti-viral immu-
Despite there being regulations oversee- cells, thereby helping viral entry into the cell. nity, while a dysregulated inflammatory
ing international wildlife trade, sceptics argue SARS-CoV-2 targets a protein on human cells, response leads to cell death and tissue dam-
that CITES (Convention on International namely angiotensin converting enzyme 2 age. Such an inflammatory response occurs
Trade in Endangered Species of Wild Flora (ACE2). It is expressed primarily in lung tis- when there is uncontrolled viral replication,
and Fauna) is simply an agreement between sue, kidneys and the gastrointestinal tract. a delay in the production of immunomodula-
nations and call instead for a complete ban The function of this important enzyme whose tors, an increased infiltration of neutrophils,
on illegal trade of wildlife. There was a failure function is to regulate blood pressure and pro- and an increased influx of pro-inflammatory
to heed the warnings of the emergence and tect the host from worsening of lung injury. On mediators. The respiratory tract is a major
spread of influenza and coronaviruses more entry into the cell, the virus is able to hijack the site of viral attack and this is supported by
than a decade ago, particularly during the host cell’s machinery for its own needs. the observation of high ACE2 expression
2009 H1N1 swine flu pandemic and during the Despite the unknowns around this novel in the lungs. Oxygen transfer between the
SARS-CoV and MERS-CoV outbreaks of 2002 coronavirus, scientists and clinicians have tiny air sacs (alveoli) and the capillaries that
14 | Nature India COVID-19 Special | June 2020NIAID
Transmission electron micrograph of SARS-CoV-2 virus particles.
Nature India COVID-19 Special | June 2020 | 15Comment
DAVID TALUKDAR/ MOMENT UNRELEASED/ GETTY IMAGES
Medics wearing protective suits in a swab sample collection centre.
line the alveoli is impeded due to an influx SARS-CoV-2 may also be striking the cardi- where there is a high expression of ACE2.
of inflammatory mediators and cells. This ovascular system: there have been reports of Patients suffering from kidney failure are more
results in the formation of dead cells along heart attacks and ischemia (blood vessel con- susceptible to acute kidney injury (AKI) as a
with pus, which contributes to the clinical striction) in fingers and toes. It is suggested result of infection.
presentation of coughing, fever and shal- that the virus attacks blood vessels and cardiac Another worrying target is the central
low breathing, leading to pneumonia. Oxy- muscle, with reports identifying blood clots nervous system (CNS); some patients have
gen therapy alleviates symptoms for some lodged in the lungs and brain. This leads to pul- reported loss of smell and developed strokes
patients, who are able to recover, while oth- monary embolism and stroke, respectively, or seizures. These symptoms suggest the virus
ers struggle, a fall in blood pressure ensues, which have been one of the major causes of has penetrative power into the brain and spinal
vascular leakage occurs, blood clots form, morbidity in critical patients. It is thought that cord or these symptoms manifest as a result of
and organ failure sets in. This immunological there are other targets on the cardiovascular the dysregulated immune response. A combi-
cascade of events results in acute lung injury system, which are yet to be identified. This is nation of both would most likely be the case as
(ALI) and acute respiratory distress syndrome of importance in the case of patients suffering SARS-CoV was able to enter the CNS and cause
(ARDS). Ultimately, pulmonary infiltration of from hypertension, diabetes, and chronic lung encephalitis.
inflammatory cells and mediators is the disease, as they are considered to be more vul- Patients have also reported diarrhoea, vom-
major cause of fatality in severe SARS-CoV-2 nerable to such attack. iting and abdominal pain, which was most
infections. The kidney is another target of SARS-CoV-2, often diagnosed as a stomach bug, but when
16 | Nature India COVID-19 Special | June 2020You can also read
