Bismillah, alhamdulillah: with information flying rapidly around from ‘drink water often to prevent the spread of the new corona virus’ to ‘don’t order anything from China as the virus will be spread through the ordered items’, it was time to get some facts from the virus experts at This Week in Virology (TWiV) who interviewed Corona Virus expert Dr Ralph Baric, PhD (University of North Carolina) who was interviewed by the TWiV team. This my quick summary with some supplemental notes to explain concepts that may have receded into medical memories.
Written for a medical target audience, numbers are time stamps from the podcast, full link at the bottom.
Corona Virus (CoV)
1. In the 22st century we have had 3 new corona viruses
2. 2003 “SARS”, 2012 “MERS”, 2019 “2019 novel CoV”
3. ‘It seems that CoVs are on the march’
4. 2019-nCoV – first few cases
– 1st case happened in Dec 2019
– Jump in reported cases 12-15th Jan 2020
– 845 cases and 26 deaths
5. 2019-nCoV is like the SARS virus
– same family ie SARS, though distantly related genomically
– SARS causes ARDS – which is difficult to treat
– 2019-nCoV is like SARS as it causes ARDS
6. SARS mortality by age
– <21y negligible
– >65y 50% (MERS >65y mortality 70%)
– Overall 10%
7. 2019-nCoV todate
– >65y mortality is majority
– This is the signature of SARS ie deaths in elderly
– 2019-nCoV MAY be slightly less pathogenic than SARS
8. Outbreak is still early
9. 2019-nCoV genome published form 5 isolates on 9/1/20
10. WuHan (where the outbreak has started) is at the forefront in virology
11. Does human-human transmission occur?
– Lancet paper published
– Wife had first infection on 29/12/19
– All family members infected by 4th Jan ie 6 days
12. Quarantine in WuHan
– 10 cities have been locked down
– 32 million people
– BUT WuHan is the central hub for trains in China
– Over 400,000 people passed in and outof the city of WuHan by train in the day before the lock down.
– i.e. quarantine effectiveness not clear
– SARS mainly spread from hospitals, which became amplifying hubs
– SARS infectivity was after 24-36 hrs after clinical symptoms
– MERS: hospital infections of Health Care Workers was key
– BUT MERS also had asymptomatic infection
– ie contact tracing was good at shutting SARS
– BUT MERS still is ongoing due to
— infectivity in asymptomatic people (impossible to track)
— infection from camels
— person-person symptomatic transmission
14. Case variability of 2019-nCoV
– 30% have severe disease
– Children: asymptomatic to mild/moderate
– This makes the disease potentially more dangerous
– Because it will spread at the community level (home, restaurant, parks etc)
– This makes it different from MERS and SARS
15. Paradoxical effect of declaration of quarantine
– People panic and try to escape the area
– Chinese car ownership has increased ie 2019 > 2003
– Road infrastructure better ie 6 lane highways
– There was a mass exodus by car
– This spreads carriers who are untraceable
16. Viral shedding of 2019-nCoV
– Lancet paper (26 Jan) goes through 41 cases
– Peak viral shedding titre days unknown
– Family cohort did not visit open market but one member went to hospital
17. Incubation period
– 5-6 days from infection
18. The Hunan market
– SARS is a 2B Corona virus, a bat virus
– SARS infected raccoons and civets (both are delicacies in S. China)
– Initial hypothesis was transfer occurred bet humans-raccoons/civets
– Viral replication in civets is well studied
– Civets are farmed in China, those fed coffee beans are a delicacy.
– Raccoons/civets in the open market were the reservoir of virus
– Later showsn SARS is a bat CoV
– Bat CoV strains shown to be 1%/ 5% and 10 % different to human SARS
– Bat CoV can infect human lung cells directly (in vitro)
– Based on this: Bats have a reservoir of SARS Group 2B viruses that can move between species.
19. 2019-nCoV v SARS
– 2019-nCoV 22% different to SARS
– Did WuHan cycle through animal?
– WuHan market sold rat meat, civet, raccoon and snake (illegal)
– Hypothesis is that 2019-nCoV went to humans directly from bats or via an intermediary host
– No bat meat sold there according to Chinese authorities.
– Live animals are sold in China i.e. – Walmart food section in China you has live turtles
20. Source of species – hypotheses
– Rural farmers who live near bat caves could have been infected by bat viruses, studies show they are seropositive for bat viruses.
– Or it could be through an intermediary animal in the open markets
– Fish is unlikely.
– Snake: one paper suggested that a snake CoV may be the source. But thought unlikely as no Group 2B isolated from a snake.
21. Patient Zero
– The initial patients in China worked in the open markets
– WHO: 23 full genome sequences with little variation
– This point to a single source.
22. Why is CoV become more ‘popular’ ie more human infections?
– Global population of over >65y = 800 million
– CoV replicates better in >60-65y
– Their transmission is not as good as other respiratory viruses
– High population densities help the CoV
– Colonization of the human host requires 8-10 transmission cycles
– Diminishing wild life habitat increases contact between animals and humans
23. 2019-nCoV receptor
– 2019-nCoV is shown to bind to ACE2 receptors to gain entry into human cells
– SARS also binds to ACE2 but its binding domain is different, so predicting the intermediary host is not easy ie it may not be civets/raccoons.
– ACE2 receptors are found in vascular endothelial cells of the heart and the kidneys
– ACE2 enzyme degrades Angiotensin II to Angiotensin 1-7 (a vasodilator)
23a. [Quick Reminder on RAA]
–(1) ANGIOTENSINOGEN (from liver, converted by serum renin from kidney) to
–(2) ANGIOTENSIN I (converted by ACE in lungs and kidney) to
–(3) ANGIOTENSIN II (binds to AT1 receptors in kidney & vascular endothelium)
— ANGIOTENSINOGEN II & ANGIOTENSIN I are degraded by ACE2 enzyme
— ACE2 sits in cellular borders mainly in heart, kidney
— ACE2 is upregulated in heart failure
— ACE2 can be made in human cells and is secreted into plasma and taken up by other cells.
24. Understanding Spread
– They were present in SARS
– They infected many patients
– A person infecting 12 patients = super spreader
– Spreadability is measured by R0 (‘R – zero’ or ‘R-O’)
– R0 = number of new infections from one infected case
– If R0<1 : number of new cases will go down
– If R0=1 : disease becomes endemic (stable)
– If R0>1 : It keeps spreading.
– SARS R0 = 1.5 – 2.5
– 2019-nCov R0 = WHO say preliminary 1.4-1.5 (25th Jan 2020)
– BUT spread in family happened to 6 so real R0 may be higher.
– Measles R0=15 (if unvaccinated population)
– Influenza R0=12 (if unvaccinated population)
– Effective R = R0 x susceptibility factor
— Example: If half of population immune then susceptibility = 50%
— So Influenza real R = 12 x 0.5 = 6
– Many trials have shown no success for MERS
– MERS Ongoing trial with Lopinavir/Ritonavir/Interferon Beta-1b
– Remdesivir (iv only) reduces ARDS in rat models (prophylactic and therapeutic) compared to triple therapy in MERS and in-vivo for GroupB nCoV
– BUT drugs workif given day 1 & 2 for these rats.
– ARDS occurs in MERS/SARS at day 8 ?possible option in the future.
26. Virus Isolate
– China has isolated the virus
– Only isolated virus in the world
– Still years away
– Phase 1 trial later this year
– MERS vaccine for camels with a recombinant vaccine, it may be a basis for developing a new vaccine
28. China’s speed
– reported SARS after 86 days from 1st case
– reported 2019-nCoV 23 days (from 1st patient with pneumonia to report)
29. Virus replication and mutation
– SARS-CoV 29 nt deletion reduced replication in vitro
– But this mutation is sustained during the whole SARS outbreak
– Mutations may make a virus more virulent
– Example of inc. virulence : OPV replicates in the gut and become more virulent through reversion and recombination TWiV 1:07:30)
– Example of less transmissible as in Ebola through mutation
– BUT no increase virulence demonstrated for natural virus infections