Episode 299: Relaxation of COVID measures and new vaccines in China part 2
Based on information from a friend-colleague in Shanghai and my own further exploration, I will discuss a few more papers to get some insight in the recent evolutions and prospects in China.
Par 1 Clinical characteristics of omicron in China and the effect of inactivated vaccines
Ep 299-1: Qinggang Li Front Med Oct 2022: Comparison of clinical characteristics of hospitalized Delta and Omicron patients in Anyang City Henan Province
Retrospective study comparing admissions of 103 Delta patients (2021) and 384 Omicron patients (Jan 2022: BA.1 ?)
From Table 1 it is evident that Omicron patients tended to be younger, had received more doses of a vaccine and presented with less comorbidities. Not surprisingly, from Table 3 it is clear that fewer Omicron than Delta needed oxygen and intensive care. There were no deaths in either group, but the duration of hospitalization and of disease was shorter for the Omicron patients.
Ep 299-2: Pei Ying-hao Front Cell Infect Microbiol Oct 2022 Predictors of severity Omicron in Shanghai
Retrospective study on over 25,000 patients in April 2022 (BA.2.2 period): only 39 showed severe disease (0.15 %)
Were positively associated with severity: taste disorder, fatigue, fever, co-morbidity and age.
- Cough negatively associated with severity
- Vaccination NS, although 2 doses univariate negative association (as could be expected)
Ep 299-3: Hongqin Xu Emerg Microb Infect Nov 2022: Real world effectiveness of inactivated COVID-19 vaccines against Omicron mild disease, pneumonia, and severe disease April-June 2022
2968 SARS-CoV-2 infections: 1029 ASY; 1858 mild; 108 pneumonia (= 3.6 %); 21 severe disease (= 0.7 %)
A = Vaccine effectiveness against pneumonia or severe disease = very significant if 2 or 3 doses
B = VE against any symptomatic disease = absent
The type of inactivated vaccine (Coronavac or BBIPB-Corv) is not important.
Ep 299-4: Chen Yu Front Pub Health Nov 2022: Impact of vaccination on the Omicron wave in Shanghai
Retrospective study on > 3000 patients with either positive PCR or symptomatic infection between 1 April and 30 May 2022.
Considered “vaccinated” if received at least 1 dose of either inactivated or recombinant protein vaccine.
LOS = Length Of Stay (in hospital) is shorter and more ASY cases in vaccinated group, especially in older patients.
- The differences are significant, but not spectacular
- Non-vaccinated presented more co-morbidities (although difference for each single co-morbidity was NS)
- The paper does not mention severe disease or death. Apparently none?
Despite the limitations, the data show that the omicron wave in Shanghai was rather mild, even in unvaccinated subjects.
- All these “real world” studies are subjected to bias, but it seems that the Omicron waves resulted in rather mild disease with < 1 % severe cases.
- The classical risk factors for severe disease (age, co-morbidities) emerge, but also taste disorder, fever, fatigue.
- The preventive effect of at least 2 doses of inactivated vaccine is not really consistent, but the time since vaccination could have a role (was not really clear).
Par 2: More on the recent “easing” of the zero covid policy
Ep 299-5: China Health Commission website 7 Dec 2022: Official policy of 10 “Optimized Prevention and Control Measures”.
- Limitation of high-risk areas
- Limitation of PCR (replacing by antigen test), less travel restrictions and less necessity for “test-negative certificates”: only in “special places” such as nursing homes, welfare homes, medical institutions, childcare institutions, and primary and secondary schools, but NOT any more for cross-regional migrants
- Home isolation of positive cases (instead of elsewhere)
- Limitation in time of closure: if negative for 5 consecutive days, unblock the area
- Pharmacies around the country must operate normally
- Accelerate the vaccination of elderly
- Identify persons with higher risk (e.g. elderly suffering from co-morbidities)
- Ensure the normal operation of society and basic medical services
- Provide convenience for the elderly living alone, minors, pregnant women, disabled people, and patients with chronic diseases. Strengthen the care, care and psychological counseling for closed personnel, patients and front-line staff.
- Schools with epidemics must accurately delineate risk areas, and normal teaching and living order must still be guaranteed outside the risk areas. Schools without epidemics must carry out normal offline teaching activities, and supermarkets, canteens, stadiums, and libraries on campus must be open as normal
In other documents, I read, there is also a call to the people to take more responsibility and act reasonably
My interpretation: It seems that the authorities are trying to keep vigilance, but avoid over-reacting by local authorities. While infected individuals are still to be isolated, they can do so at home and take up their activities when they are consistently negative. Society should be as open and normal as possible, but there is special attention for elderly and vulnerable people.
Ep 299-6: Associated Press 9 Dec claims that as a consequence of less testing, official figures, showing a fall in cases, no longer reflect the true numbers and that in fact infections and sick people rise sharply
Social media users in Beijing and other cities said coworkers or classmates were ill and some businesses closed due to lack of staff. It wasn't clear from those accounts, many of which couldn't be independently confirmed, how far above the official figure the total case numbers might be.
Par 3. More on novel Chinese vaccines
Ep 299-7: Press release by the National Institute of Biological Sciences on 5 Dec describes four vaccines that have been approved for “emergency use”: 3 of those are recombinant Spike proteins
- Vixin, by Sichuan University and Chengdu Wesker Biological Co., Ltd : based on expression in insect cells. It is not clear if it is based on Wuhan strain, if it is monomeric or trimeric and no clinical trials are mentioned, but it is said to be safe. I failed to find published data.
- SCB-2019 by Hong Kong Clover Bio Co. is certainly the most advanced. It is a trimeric S, based on the original Wuhan strain with CpG1018/aluminum adjuvant. While alum is a very traditional B-cell stimulating adjuvant, CpG is supposed to stimulate T cell immunity as well. There is a lot of published data (see below).
- SCTV01C, developed by Beijing Shenzhou Cell Biotechnology Group Co., Ltd (SinocellTech), is a 2-valent (Alpha/Beta variant) S trimer protein vaccine with an oil-in-water adjuvant for T cell stimulation. There are 3 papers on this vaccine (see below)
The fourth vaccine CA4-dNS1-nCoV-RBD is a nasal spray COVID vaccine, based on an attenuated Influenza virus vector. It is being developed by Xiamen University, the University of Hong Kong and Beijing Wantai Company.
Par 3.A The S protein-based vaccines
3.A.1 SCB-2019 (Clover) = trimeric wild-type S protein
Ep 299-8: Richmond Lancet 2020 Phase 1 study
Strong neutralization of WT virus max 14 days after 2 doses. AS03 adjuvant seems better than CpG/Alum
Ep 299-9: Lulu Bravo Lancet Jan 2022 SPECTRA = phase 2 and 3 Study evaluating Protective Efficacy and safety of Clover’s Trimeric Recombinant protein-based and Adjuvanted COVID-19 vaccine.
The 30 µg dose with CpG/Alum was used (no explanation why this adjuvant was preferred over AS03)
Very high efficacy against severe disease, more effective against gamma than delta, slightly less active > 60 yrs
Ep 299-10: Igor Smolinov Lancet April 2022: Effect of hybrid immunity within SPECTRA
- Before the Omicron, there was a strong protective effect on re-infection by previous infection.
There is an additional protective effect of one (A) and two (C) doses of SCB-2019
Ep 299-11: Donna Ambrosino J Infect Dis Nov 2021 compares binding antibodies to WT and Alpha Spike between the mRNA, Adeno vaccines and SCB-2019:
Clearly, responses to SCB-2019 were significantly higher than both ChadOx1nCoV-19 (Astra-Zeneca)n and Ad26.COV2.s (Janssen) vaccine groups (P < .0001) and significantly lower than mRNA-1273 (Moderna) (P < .0001) and BNT-162b2 (Pfizer) (P = .0009) vaccine groups for both original and Alpha variant.
Ep 200-12: Tadesse CID 2022: SCB-2019 reduces transmission in households by 70-80 %
Ep 299-13: Rao medRxiv Dec 2022: SCB-2019 as heterologous booster induces superior neutralizing antibodies against Delta, BA.1, BA.2, BA.4, BA.5 as compared to homologous booster (9 months after 2 doses with CoronaVac)
3..A.2. SCTV01C (Sinocelltech)= 2-valent (Alpha/Beta variant) S trimer protein with an oil-in-water adjuvant
2. 1. Preclinical studies
Ep 299-13: Rui Wang Vaccines April 2022: Induction of cross neutralizing Ab against a range of VOC in mice by the bivalent SCTV01C > monovalent beta (B.1.351) > monovalent alpha (B.1.1.7) vaccine
Ep 299-14: Rui Wang Viruses 2022: Evaluation of protective efficacy and cross-neut against omicron subvariants
- Both the beta (B.1.351) monovalent and the bivalent SCTV01C induce neutralizing Ab and protect against challenge with SARS-CoV-2 beta in ACE2 transgenic mice
- SCTV01C is superior to D614G (= wild type) in inducing neutralizing Ab against omicron subvariants (Note: responses in C57Bl mice much weaker than in Balb/c mice.
2.2. Clinical studies
Ep 299-15: Wang J Infect Nov 2022 Phase 1 clinical trial with SCTV01C two doses of 20 µg 28 days apart
→ Inductiin of strong neut Ab against a broad range of subvariants, also in > 60 yrs old
Ep 299-16: Phase 3 studies are ongoing in several countries, but no published results yet
Par 3.B Intranasal vaccine based on attenuated influenza CA4-dNS1-nCoV-RBD (= dNS1-RBD)
This vaccine is based on a Live-Attenuated Influenza Vaccine (LAIV) with a deletion within the NS gene: preserving the NEP (= nuclear export protein function), but deleting NS1, which is an interferon antagonist. By deleting the NS-1, the virus is attenuated to become non-pathogenic, but the host immune system is activated, both in its innate function (increase of type 1 IFN), but also via activation of dendritic cells, activation of adaptive T and B immunity. See Jurgen Richt Curr Top Microbiol Immunol “Vaccines for Pandemic Influenza” 2009 p. 177
Ep 299-17: Junyu Chen Sc Bull May 2022 A live attenuated virus-based intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2
In the delNS1 from H1N1 influenza virus A/California/04/2009 (= CA04-dNS1) the RBD from SARS-CoV-2 is inserted
Remarkably, intranasal administration by either the parental CA04-dNS1 or the recombinant dNS1-RBD (= CA04-dNS1-nCoV RBD) protect against SARS-CoV-2 challenge 1 day later, pointing to innate immunity (via type 1 IFN?)
However, this protective effect is long-lasting (up to 9 month after vaccination) and is also against omicron.
There is evidence that this long effect is due to adaptive responses, including mucosal IgA and T cells with broad cross-reactivity against several VOC and against Flu
→ Mucosal IgA and serum IgG angainst RBD
→ ELISPOT = T cell reactivity against RBD of various SARS-CoV-2 VOC and against Flu
Ep 299-18: Fengcai Zhu Lancet Resp Med May 2022 Phase 1 and 2 with dNS1-RBD (2 doses 2-3 weeks apart)
Very acceptable side effects
T cell responses as well as Ab responses in peripheral blood rather weak
Phase 3? In the press release by the National Institute of Biological Sciences (Ep 299-7) we read the following:
The phase III clinical trial was also unblinded on October 7 this year, and the research data showed that the vaccine has a good protective effect and excellent safety against symptomatic infection caused by the Omicron strain.
I could not find a formal publication or a preprint with these data
Par 3 C: Another mRNA vaccine Svirk by Siwei company
See Ep 299-19 Press release. Unfortunately, I could not find any scientific information
GENERAL CONCLUSION Episodes 298 and 299
The Chinese authorities have eased the zero COVID, under popular pressure and because they are convinced that the present omicron variants will not cause much severe disease in a population, which has a partial immunity by inactivated vaccines. The crucial need for a rapid booster with a different type of vaccine is, however, recognized.
There is a number of more innovative Chinese vaccines based on several technologies:
- 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.
- mRNA vaccines: ARCoV (AWCorna) and Svirk. Clinical studies with ARCoV are promising, but no published data on Svirk
- 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.
7 May 2023 Episode 332 Critical evaluation on COVID vaccine effectiveness during successive omicron waves
> More info
4 April 2023 Episode 326 Adeno-associated viruses as a cause of hepatitis and as a tool for gene therapy
> More info