4 dec 2022 Episode 298 What after the zero COVID policy in China?

Episode 298: The end of China’s zero COVID policy, but… what next?

Dear colleagues,

China has controlled the SARS-CoV-2 epidemic in a very remarkable -in fact unique- and successful way during 2.5 years by strictly applying “non-pharmacological interventions” at an unprecedented scale.  Very unfortunately, this opportunity was not fully used to completely vaccinate the enormous population (and especially the elderly) against this virus that keeps on escape-mutating and increasing its infectivity. We cannot know what the psycho-social price of this strategy has been, but we have observed and experienced the economic backlash.

China has been betting mostly on inactivated vaccines with limited duration of protection and, apparently, has not made deals with Western companies to access more potent and durable mRNA or vector vaccines. As we will see, China has developed its own version of these types of vaccines, preclinical and early clinical results have been published and are encouraging, but these vaccines have not yet been widely rolled out.

Over the last week, we have seen these very unusual pictures of large-scale protest against the harsh lockdown measures in Chinese factories and cities (with protesters wearing face masks!). And we heard in the mainstream media that the Chinese authorities “are giving in” and plan to “mitigate the zero COVID policy”.  But what does it really mean and how would the Chinese health authorities prevent a massive COVID outbreak?

Starting from a short paper in Nature Briefing and some very recent official documents from China, we will explore the challenges and options…

Par 1 Setting the scene

Ep 298-1:  Smriti Mallapaty Nature Briefing indicates that on Nov 29 there was a height of 71,000 cases of the BF7 variant (which is also prevalent nowadays in US).

Easing the restrictions will require to rapidly ramp up the third vaccination, since only 69 % of Chinese over 60 and only 40 % of those over 80 have received a third dose.  In addition most were vaccinated with the inactivated vaccines, which induce only 50-80 % protection against Wuhan strain and this protection wanes rapidly (2-3 months).  Alternative vaccines are the “inhalable” intranasal vector and a Chinese mRNA (discussed later).

Ep 298-2:  Airfinity, a modeling company, is not very reassured.  They compare the situation in Hong-Kong, where 34 % of the 60 + were vaccinated in Feb, when the omicron wave hit and a high mortality was observed. Based on the rather low vaccination in mainland China, they estimate that lifting restrictions now could result in between 167 and 279 million cases and between 1.3 and 2.1 million deaths nationwide.

Ep 298-3 and -4: Two official sources from Digital Economy Think Tank and Financial News (originally in Chinese, machine translated)

Some excerpts

Vice Premier Sun Chunlan pointed out that the pathogenicity of Omicron virus has weakened, vaccination is more popular, and experience in prevention and control has been effectively accumulated….

The number of cases has increased, but there have not been a large number of critical illnesses and deaths. This shows that China's anti-epidemic policy has withstood the worst period of the virus; The people are protected to the greatest extent; this shows that China's anti-epidemic policy has actually won. We have not seen the tragic social scene in the West.

We must try to protect people's livelihood on the premise of preventing the epidemic, and we must try to prevent the epidemic under the conditions of normal economic life.

Under such circumstances, we are going to face a new situation in epidemic prevention and control, which requires us to have more scientific and rational new epidemic prevention and control policies.

….

What impressed me the most were the following three pieces of news:

• First, the domestic scientific research team experimentally verified that the pathogenicity of Omicron has been greatly reduced.
• Second, experts say that there is currently no evidence that the COVID-19 has sequelae.
• Third, the doctor of Beijing Ditan Hospital: Young people who are infected with the Omicron mutant strain generally do not have fever for more than 3 days.

According to a Caixin report, the target has now been lowered: by the end of January, the vaccination rate of the first dose of the COVID-19 vaccine over the age of 80 will reach 90%!

The mortality rate of people over the age of 80 infected with the COVID-19 is 14.70% if one dose of vaccine is not vaccinated. If three doses of vaccine are given, the mortality rate will immediately drop to 1.58%, and four doses will drop to 0.87%,  Therefore, the key now is to let the elderly get vaccinated as soon as possible.

…

It is very clear: everyone must take care of themselves. This winter is coming again, and the pandemic has been going on for three years. The country is exhausted, and the people are exhausted. We have finally reached this crossroads. The direction is clear, and I firmly believe that after continuous optimization and even liberalization, our economy will soon usher in a big rebound, and there will never be a lack of supplies and collapse as many people say. There is no reason, because I believe that the passion and motivation of Chinese people to make money is unparalleled in the world. As long as you don't limit it, they will create miracles. The green mountains can't cover it, after all, it's going eastward! I believe that the Chinese who have experienced countless storms and waves are fully capable of surviving the last test of the fight against the epidemic!

My interpretation: China wants to resume its economic activity and beliefs that omicron is a weaker virus.  The younger generations should no longer live under restrictions and the old ones should be protected by rapid vaccination.

Par 2 Are the more recent omicron variants less pathogenic?

It is very difficult to answer this question.  For sure, we see (much) less hospitalizations and deaths during the successive omicron waves as compared to one or two years ago, when delta resp. alpha-beta-gamma were predominant, but in the whole world (except China) most people (except very old, frail and/or immune suppressed subjects) enjoy a rather good degree of immunity, induced by vaccination and/or infection.

In addition, the relatively homogenous successive epidemic waves in 2020 and 2021 have now been replaced by much more complex mixtures of omicron subvariants

It has been suggested that the successive mutations increase infectivity, which sounds logical, because the virus has to infect people, which have neutralizing antibodies.

Some clinic-epidemiological observations

Ep 298-5:  Paul Morris medRxiv 23 Sept 2022: Omicron Subvariants: Clinical, Laboratory, a  Cell Culture Characterization at Johns Hopkins (US)

The BA.1 was associated with the largest increase in SARS-CoV-2 positivity rate and COVID-19 related

hospitalizations. After a peak in January cases fell in the spring

The emergence of BA.2.12.1 followed by BA.5 in May 2022 led to an increase in case positivity and admissions.

BA.1 infections had a lower mean Ct ( = higher viral load) when compared to other Omicron subvariants. BA.5 samples had a greater likelihood of having infectious virus at Ct values less than 20: hence more infectious.

But those are just observations; what do they mean in terms of pathogenicity, irrespective of immunity.

Ep 298-6: Joseph Lewnard 3 Nov 2022 tries to correct for prior vaccination and infection and finds a similar pathogenicity for BA.5 as compared to BA.2.

BA.4/BA.5 cases had 15% higher adjusted odds of having received 3 and ≥4 COVID-19 vaccine doses, respectively, than time-matched BA.2 cases, as well as 55% (43-69%) higher adjusted odds of prior documented infection.

However, after adjusting for differences in epidemiologic characteristics among cases with each lineage, BA.4/BA.5 infection was not associated with differential risk of emergency department presentation, hospital admission, or intensive care unit admission following an initial outpatient diagnosis.

Ep 298-7: Eric Topol 4 Dec 2022 The new COVID wave leads to more hospitalizations in US and other countries

Eric Topol sees four reasons (in US):

1. Waning immunity
2. Abandonment of mitigating measures (masks, ventilation, crowds…)
3. The rise of the BQ.1.1 variant
4. Low Paxlovid uptake  

All this background information is interesting, but does not really answer the question about intrinsic pathogenicity.

To that end, we can look at the animal model of infecting truly naïve hamsters

Ep 298-8: Tomokazu Kamura bioRxiv 5 Aug 2022 Comparative pathogenicity of SARS-CoV-2 1 Omicron subvariants including BA.1, BA.2, and BA.5

All omicron variants seem less pathogenic than the reference ancestral B.1.1 (close to Wuhan), but BA.5 maybe more pathogenic than BA.1/2

• Only B.1.1 results in loss of body weight and bronchoconstriction (= increase PenH and decrease Rpef)
• However: BA.5, just like B.1.1 results in temporary drop of oxygen saturation (SpO2)

BA.5 has a high index of histopathology (similar to B.1.1).

Inflammatory markers of BA.5 are somewhat higher than BA.1/2, but nevertheless clearly lower than B.1.1

The authors conclude: Our data suggest that BA.5 is still low pathogenic compared to ancestral strain but evolved to induce enhanced inflammation when compared to prior Omicron subvariants.

Ep 298-9: Uraki bioRxiv 28 Aug 2022 Characterization of SARS-CoV-2 Omicron 1 BA.2.75 clinical isolates:

Delta is clearly more pathogenic than all omicron variants

• No substantial differences in weight change among hamsters infected with BA.2, BA.5, or BA.2.75,
• The replicative ability of BA.2.75 in the lungs was higher than that of BA.2 and 44 BA.5.
• BA.2.75 caused focal viral pneumonia in hamsters, characterized by patchy inflammation interspersed in alveolar regions, which was not observed in BA.5-infected
• In competition assays, BA.2.75 replicated better than BA.5 in the lungs of hamsters.

These results suggest that BA.2.75 is “fitter” (has a higher replication capacity)            and can cause more severe respiratory disease than BA.5 and BA.2 and should be closely monitored.

My conclusion: Although is a different outcome in both experiments with regard to BA.5, it seems however clear that all omicron subvariants are less pathogenic than either the “original” B.1.1 and the Delta variants.

Nevertheless, the relatively high mortality in largely unvaccinated  Hong Kong elderly during the Omicron BA.1/2 wave as opposed to low mortality in mostly fully vaccinated inhabitants of Singapore and New Zealand reminds us that Omicron is not necessarily an innocent virus in a “naïve population”.

Par 3 What about the inhalable (intranasal) vaccines “made in China or India” ?

Ep 298-10: Emily Waltz 15 Sept in Nature announces that China and India have tested adenoviral vaccines for intranasal administration in humans successfully, but no clear data on phase 2 or 3 are presented. 

Hence I screened the peer-reviewed and preprint literature.  This is what I found:

1. Chinese vaccine based on human Adenovirus serotype 5

Ep 298-11: Liqiang Feng Nat Comm  2020 An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques

The construct is based on classical Human Adeno 5 with deletion of E1 and E3  and with the Spike DNA in E2 position

Experimental set-up: IM = intramuscular; IN = intranasal

Immunogenicity:  SFC = spot forming units in ELISPOT (= production of IFN-g by T cells) right under

The antibody and T cell (SFC = ELIspot) in the blood are somewhat weaker after intranasal (IN) immunization

Protection:

Intranasal immunization protects against challenge (although the animals had no detectable neutralizing antibodies before challenge)

The authors speculate that intranasal immunization could circumvent the disadvantage of pre-existing serum antibodies against Adeno 5 in many human subjects and thus be more effective than IM.

Moreover, the administration of Ad5 vectored vaccines through nostrils may make self-vaccination possible, thus reducing the burden of healthcare workers and enabling more people to receive a vaccine within a short timeframe.

Ep 298-12: Zhe Zhang medRxiv 22 March 2022 Aerosolized Ad5-nCoV booster vaccination elicited potent immune response against the SARS-CoV-2 Omicron variant after inactivated COVID-19 vaccine priming

The IN Ad5 as a booster 6 months after inactivated Coronavac was compared with three other boosters: 5 X higher Ad5 IM, the dimeric receptor binding domain subunit (ZF2001 or Zifivax) and Coronavac

Aerosolized Ad5-nCoV was superior:

1. The greatest neutralizing antibody responses against the Omicron variant at day 28 after booster at 14.1-fold that of CoronaVac, 5.6-fold that of ZF2001 and 2.0-fold that of intramuscular Ad5-nCoV.

2. The IFNγ T-cell response to aerosolized Ad5-nCoV was 12.8-fold for CoronaVac, 16.5-fold for ZF2001, and 5.0-fold for intramuscular Ad5-nCoV

I could not find results of phase 3

2. Indian vaccine based on Chimp Adeno 36 vector

Ep 298-13: Ahmed Hassan Cell Oct 2020 A Single-Dose Intranasal ChAd Vaccine Protects MICE Upper and Lower Respiratory Tracts against SARS CoV-2.

Intranasally (but NOT intramuscularly ) delivered ChAd-SARS-CoV-2 uniquely prevents both upper and lower respiratory tract

infections, potentially protecting against SARS-CoV-2 infection and transmission.

Ep 298-14: Announcement by the Indian Ministry that this vaccine (now called BBV154 and produced by Bharat Co.) has successfully ended human phase 1, 2 and 3 trials and therefore is approved for human use.  However, I could not find the result of these trials.

Par 4 What about Chinese mRNA vaccine: ARCoV or AWcorna?

Ep 298-15: Na Na Zhang Cell Sept 2020 A Thermostable mRNA RBD vaccine against SARS-CoV-2

Development of LNP-encapsulated mRNA vaccine (ARCoV) targeting the RBD of SARS-CoV-2 thermostable at 2-8 )C

• ARCoV induces neutralizing antibodies and T cell immunity in mice and NHPs
• ARCoV vaccination confers full protection against SARSCoV-2 challenge in mice

Ep 298-16: Gui-Lin Chen Lancet Jan 2022 : Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults (Phase 1): dose-escalation prime-boost (day 0 and 28)    

Neutralizing Ab against live virus induced at a similar level as in convalescent serum

No clear-cut  dose-response effect.

Conclusion: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.

Ep 298-17: Xiao-Feng Li Human Vaccines & Immunotherapeutics July 2022:  Neutralization of ARCoV-induced sera against SARS-CoV-2 variants

Well preserved neut against live virus (b), with lowest activity against beta (as expected, based on other vaccines).

Ep 298-18: Xiaoqiang Liu medRxiv May 2022:  Safety and superior immunogenicity of heterologous boosting against delta and omicron with an 1 RBD-based SARS-CoV-2 mRNA vaccine in Chinese adults

Fig.1 GMT of neutralizing antibodies to live wild-type SARS-CoV-2 or Delta variant.

Fig.2 GMT of neutralizing antibodies to Omicron variant

Overall conclusion

The Zero COVID policy is no longer realistic and China has developed a valuable intranasal Adenoviral vector vaccine as well as a good RNA vaccine (to be administered IM, but apparently easy to keep at frig T°).  The results of animal and early human  trials are encouraging, in that protective immunity can be induced in animal models and these vaccines can effectively boost the weak immunity from previous inactivated vaccines in humans, including against the (early) omicron variants. 

However:

• Results of phase 3 trials have not been published.
• There is no mentioning about omicron-adapted vaccines.

It is therefore not clear how antibody titers translate in clinical protection against severe disease by the latest omicron subvariants

Above all, how fast should one vaccinate the hundreds of millions of older Chinese residents (many of whom have not even received a full course of the inactivated vaccines) to prevent a massive epidemic with relatively high mortality, as we have seen in Hong Kong during the Spring.

I can only guess, but I wholeheartedly hope that the latest omicron subvariants are indeed less pathogenic in relatively naïve people and that the Chinese health authorities will be able to roll out the new vaccines at an unprecedented pace and with a superior “phase 4” result as well…

Best wishes,

Guido