4 January 2023 Episode 303 China today

Episode 303: Chinese COVID 2023

Dear colleagues,

Nowadays, everybody is worried about China. After almost 2 years of “zero COVID”, with a remarkable control over the viral spread, the policy was suddenly changed to almost no restrictions. Together with Geert Molenbergh, Pierre Vandamme, Patrick Smits and a personal contact in Shanghai, I have been trying to put all the “alarming news” in a context. The first paragraph is on Epidemiology, but I will also come back on Chinse vaccines and drugs in development.   

I will critically compare China’s epidemic with those in other former “zero COVID countries and compare the expected evolution in China with the US.  I will also try to understand the scientific background of proposed vaccines and therapies.

Par 1 Epidemiology

Articles in The Economist (Ep 303-1); Force of Infection (-2); Financial Times (-3) and Science (-4), all agree that the epidemic is growing out of control after releasing all measures very quickly, because the population is under-vaccinated and there is not enough intensive care capacity.

With regard to vaccination: China on December 1, 2022: 92% (1st dose)- 89%  (2nd Dose) - 57% (3rd dose), but almost exclusively inactivated vaccines and with the last booster many months ago.

With  regard to ICU capacity: there are no reliable numbers. The Economist quotes “officials”: 10 ICU beds per 100,000 people.  As a comparison, the ratios in Europe are between 190 (Sweden) and 600 (Germany) with Belgium at 500 per 100,00. See https://tradingeconomics.com/country-list/icu-beds?continent=europe   

This situation may worsen, when Chinese people will massively travel around at the occasion of the Chinese new year later this month

Unfortunately, there is essentially an information stop in China, since the official numbers of infections and deaths are incredibly low. 

There is a fear that in such an explosive epidemic new variants may arise, but that is not yet the case.  According to ECDC (Ep 303-5), 437 recent sample collection dates between  1 and 24 December 2022 in GISAID EpiCoV. mainly belonged to the lineages BA.5.2 (35%), BF.7 (24%), BQ.1 (18%), BA.2.75 (5%), XBB (4%), BA.2(2%).   

These subvariants are not a new threat for Europe (as they already circulate here). Hence the conclusion :  Given higher population immunity in the EU/EEA, as well as the prior emergence and subsequent replacement of variants currently circulating in China by other Omicron sub-lineages in the EU/EEA a surge in cases in China is not expected to impact the COVID-19 epidemiological situation in the EU/EEA.

As you know, there is a lot of political debate on travel restrictions from China and pre-travel testing.

The following graphs from Ep 303-2 may help to judge its value

As you can see, whatever test is done, it reduces the likelihood of post-travel transmission by maximum 10 % and only if done max 24 H before arrival….

Comparison with other “Zero Covid” countries (see Ep 303-6 and 7 by Geert Molenbergh and Pierre Van Damme)

Besides China, also Hong-Kong, Taiwan, Singapore, Australia and New Zealand had a zero COVID policy until beginning of 2022.  Afterwards, infections rose, but only in Hong-Kong there was also a sharp rise in mortality

Note: the mortality graphs in Australia, New-Zealand Taiwan are rather similar to those of Singapore, hence remaining lower than in Europe or US, even after lifting restrictions.   

WHY Is that?

First the release from zero covid policy in all these countries was more gradual than it is now in China.

On March 1 of 2022, the vaccination rate was (received at least 1 vaccine; fully vaccinated / received 1 booster):

Hong Kong: 83% - 70% - 23%

Taiwan: 81% - 75% - 42%

Australia: 84% - 78% - 44%

New Zealand: 82% - 76% - 47%

China: 89% - 87% - 39%

Singapore: had 65 % boosted on March 1

Clearly, Hong Kong was not only lagging in proportion boosted, but had also largely relied on less durable inactivated Chinese vaccines and the older population was vaccinated much less.

(Unfortunately, no data for Singapore, but overall vaccination rate much higher and mostly by more powerful vaccines than in Hong Kong).

Projections for China and US in 2023 according to the Institute of Health Mectrics Evaluation (IHME) https://covid19.healthdata.org/china?view=cumulative-deaths&tab=trend

China (population 1420 million)

To be compared with USA (population 327 million)

Estimated total death toll per million by April 2023 is only 227 in China versus 4,425 in US, thus 20 X higher in US.

Par 2 Vaccines

See Ep 298-299.  My conclusions are still valid:

… The crucial need for a rapid booster with a different type of vaccine is recognized.

There is a number of more innovative Chinese vaccines based on several technologies:

1. Recombinant S proteins: SCB-2019 (Clover) and  SCTV01C (Sinocelltech).  Both are solid candidates, but only Clover has published phase 3 results. Also Vixin is mentioned, but no publications. 
2. mRNA vaccines: ARCoV (AWCorna) and Svirk.  Clinical studies with ARCoV are promising, but no published data on Svirk
3. Intranasal vaccines: based on Adeno5 or Attenuated Influenza are also promising, but no  phase 3 results are available.  

Most of these vaccines have received emergency use approval, based on largely non-published results. It is likely that they are already in mass production and it is evident that Chinese health authorities are determined to roll out these boosters as quickly as possible in the most vulnerable individuals (mainly elderly).

However, it is difficult to predict how successful this policy will be, because we lack information on the precise immune status of the most vulnerable population and, based on published data, we can only be sure about the Clover vaccine, which has shown excellent efficacy as a booster in various settings.

In the meantime, I found 1 more paper on the Chinese mRNA vaccine ARCoV

Ep 303-8: Liu medRxiv 31 May 2022 shows that ARCov (or AWcorna) has boosts neutralizing Ab against delta and omicron (presumably BA.1) much better than a third inactivated (CoronaVac) dose.

Neut titers were slightly lower in older people

Ep 303-9 to -11: According to these three press articles, since many months Fosun, a Chinese partner of Pfizer, was willing to produce the Pfizer mRNA vaccine in big lots and carry out clinical trials in China, if needed. Unfortunately, Chinese authorities turned the offer down in favor of developing their own mRNA vaccines.  The Pfizer vaccine can only be used for foreigners in China.  More recently, the EU representative offered bivalent (wild type + BA.1) mRNA vaccines (which were not used in Europe), but the Chinese authorities did not accept it.

Ep 303-12: An example of four calls in the Chinese media to get a booster, I received as a personal communication. 

As you can read, since the end of October, people are invited to get a third or fourth vaccine in a vaccination center.  Several types of vaccines are mentioned: repeat inactivated vaccine in one case,  various recombinant Spike proteins intramuscularly, recombinant Spike adenoviral vectors  for intramuscular or intranasal administration etc.  The proposed interval is 6 months. Remarkably,  the mRNA vaccines are not mentioned.

Par 3 News on treatment options

3.1 V116

V116 is a orally available derivative of Remdesivir. We described it already in Ep 279

Ep 279-13: Yuanchao Xie Cell Res 2021 Design and development of an oral remdesivir derivative

X6 = derivative further referred to as VV116: was able to suppress viral load in lung tissue of infected mice:

VV116 at 100 mg/kg shows a similar activity as Molnupiravir (EIDD-2801) at 250-500 mg/kg

Ep 279-14: Yinzhong Shen Emerg Micr Infect 2022: open prospective cohort of VV116 in Chinese COVID patients

60 patients who received VV116 (300 mg, BID×5 days) versus and 76 patients in the control group with only standard treatment.   While comparable for most parameters, the control group was more symptomatic

Participants who received VV116 within 5 days since the first positive test had a shorter viral shedding time than the control group (8.56 vs 11.13 days), and cox regression analysis showed adjusted HR of 2.37 [95%CI 1.50-3.75], P < 0.001.

NEW INFORMATION on V116

Ep 303-13: Cao  NEJM 12 Dec 2022: Among adults with mild-to-moderate Covid-19 who were at risk for progression,   VV116 was noninferior to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns.

No participants in either group had died or had had progression to severe Covid-19 by day 28.

(The trial was done in Shanghai during the BA.2 wave and 75 % of the subjects were vaccinated with at least once)

Comment: Although encouraging, these results are difficult to interpret, as there is no placebo control group.

3.2. Azvudine:  is another orally available polymerase inhibitor that we discussed in Ep 279.

Ep 303-14: Bin Yu in Innovation Nov 2022 summarizes the story.

Ep 303-15: Ren Advanced Science 2020

1. Anti-HIV: Azvudine (FNC, 20-deoxy-20-b-fluoro-40-azidocytidine) targets reverse transcriptase and HIV-1 accessory protein (Vif) simultaneously, being the first-in-class dual inhibitor In July 2021, Azvudine was approved by the National Medical Products Administration to treat adult patients infected by HIV-1.

2. Anti-SARS-COV-2

• In vitro: Azvudine inhibited SARS-CoV-2 with an EC50 value ranging from 1.2 to 4.3 mM and a selectivity index of 15–83.
• In SARS-CoV-2-infected rhesus macaque models, Azvudine reduced viral load, improved lymphocyte profiles alleviated inflammation and organ damage, recuperated the thymus, and lessened ground-glass opacities.
• In COVID patients a very small ( n = 20) open label controlled study showed a faster negativation of PCR (NAT = nucleic acid testing).  Ep

Also pneumonia incidence declined faster in the Azvudine group

Comment: according to our standards, this is rather weak evidence to approve an antiviral drug.  

3.3. Monoclonal Ab SA58

Ep 303-15:  Yunlong Cao Cell Rep Dec 2022 describes two very broad monoclonal Ab (SA55 and SA58: they were derived from SARS-CoV-1 survivors that were vaccinated against SARS-CoV-2: they neutralize SARS-CoV-1 and all omicron sublineages of SARS-CoV-2, as well as several animal viruses.

Prophylactic and even to some extent therapeutic treatment with the SA55 + SA58 cocktail protected ACE-2 mice against a challenge with a mixture of BA.1 and BA.5

Ep 303-16: Shujie Si medRxiv 31 Dec 2022: Prophylaxis against omicron BA.5 with the SA58 monoclonal in humans.

An open label blank-controlled study was performed amongst over 1700 HCW  during 30 days (Nov 2022), with an epidemic of BA-5 sublineages (BF.7, BA.5.2, BA.5.2.1, BQ.1.2) and over 3000 blank-controls.  The active group  sprayed the liquid product (5mg/ml) every 6 hours.  The calculated protective efficacy was 77 %.

The side effects were not uncommon, but considered mild

CONCLUDING REMARKS

1. While the Zero COVID policy has saved many lives in China (but also Hong Kong, Singapore, Taiwan, Australia and New Zealand), the sudden drop of all measures has resulted in a dramatic rise in cases, but most likely will it have a have high death toll in China, because the older population has not been boosted with high quality vaccines and the ICU capacity of China may not suffice. Nevertheless, even then, the death toll will presumably remain proportionally lower than in the US, but higher than in most other “zero COVID” countries.
2. Chinese academia and companies have  developed a lot of interesting vaccine concepts and also some new drugs.  The polymerase inhibitors are not really original, but the very potent and broad mAb is intriguing.  It is not always clear whether clinical trials have been performed according to international standards. 
3. From a public health perspective, it is regrettable that China has not collaborated with Western companies (e.g. Pfizer) and has not accepted the European offer to roll out potent vaccines much quicker than is done now, but we can only guess what the political and economic reasons for those decisions have been.

 Ending with a personal communication from Shanghai

1) We have COVID vaccines in Shanghai including inactivated, recombinant subunit proteins and CanSino vaccines (= recombinant Spike-expressing Adenoviral vectors) . All the vaccination programs for boosters are announced and implemented by government. The vaccination centers are setup by district health administration where people are free to get it. Sofar Shanghai recommends to use CanSino（inhale vaccine）and recombinant subunit protein vaccines for booster.  

2) As COVID drug, China has licensed Azvudine as anti-COVID. I and my wife use it. Paxlovid was just imported last month. These two drugs need to be prescribed by doctor, However I just saw a news these two drug have been distributed into community clinics for patients to get it easily (based on the doctors’ diagnosis), and meantime relieve the pressure on big hospitals , as I know the “fever out-patient clinics” are crowded now in all big hospitals in Shanghai. 

3) Although the “opening” was relatively sudden and most big hospitals may not be prepared enough, it has not yet reached the point of collapse. The medical staffs are doing their best to treat and care the infected. Hope to learn from experience and lessons for the next wave in future. 

I hope this Episode has somehow enlightened your insight on what is happening today in China.

Best wishes,

Guido