The WHO approved the emergency use of Sinopharm's new crown vaccine. What new actions are there next?

The following articles are from CC Intelligence Bureau, author Zhang Hongtao.

Introduction

On May 7, WHO approved the new crown vaccine produced by Sinopharm Group for emergency use. This is the first non-Western new crown vaccine approved. At the same time, the WHO also said it would decide next week whether to grant emergency use approval for Sinovac's vaccine.

Previously, the WHO assessed Sinopharm Beisheng Institute and Sinopharm's inactivated vaccine on April 29 and May 3, respectively. The results showed that Sinopharm and Sinopharm vaccines are highly effective in preventing adults from contracting the virus. Credible, the evidence of safety data is moderately credible.

This is the first time that Sinopharm vaccines have published clinical data. However, in the clinical trial , the elderly and people with concurrent diseases samples are relatively small, so the WHO considers that the quality of evidence is insufficient, and even very low in some aspects. The WHO considers the Sinovac vaccine evidence more credible because the data on older adults and those with comorbidities are more complete.

Compared with other vaccines, the overall evaluation of Sinovac vaccine is not as good as Moderna and Johnson & Johnson , but better than Oxford University's AstraZeneca vaccine.

The efficacy and safety of vaccines for adult protection are the main evaluation indicators, and Sinopharm and Sinovac vaccines scored the same as other approved vaccines in this regard. Coupled with the high demand for vaccines in the global epidemic situation, even if some Sinopharm and Sinovac vaccines have low scores, they will still be approved by the WHO for emergency use.

By | Zhang Hongtao (Associate Professor, University of Pennsylvania School of Medicine)

The World Health Organization evaluated the inactivated vaccines of Sinopharm Beisheng Institute and Sinopharm on May 3, respectively.

For the effectiveness of the two vaccines in preventing adults from contracting the virus, WHO considers the evidence to be highly credible; for the risk of adverse events after vaccination , WHO also considers the evidence to be moderately credible. For the elderly and those with co-morbidities, WHO considers the evidence for the efficacy of the Sinovac vaccine to be of moderate quality, but the evidence for safety is insufficient.

For Sinopharm vaccines, the quality of the evidence is considered by WHO to be insufficient, and in some respects very low, due to the small number of elderly and co-morbid populations in clinical trials.

It is also the first time for domestic media and scholars to see the data of Phase III clinical trials of Sinopharm and Sinopharm released by WHO. The claim that these two domestically produced inactivated vaccines have low evidence of so-called protection and safety in the elderly and people with concurrent diseases has obviously caused huge controversy and concern.

How should we view Sinopharm Vaccines and Sinovac Vaccines, which have lower data in the elderly and those with concurrent diseases? Does it mean that the vaccine is ineffective in the elderly and people with disease? Can the elderly and people with concurrent diseases still receive the two domestic vaccines and ? Can Sinopharm and Sinovac vaccine pass this WHO review?

It is understood that after comparing the data of Pfizer, Moderna, Johnson & Johnson and AstraZeneca vaccines published by WHO, some experts said that the data of these two inactivated vaccines in China are "not too perfect", but they are still better than The numbers for AstraZeneca's vaccine are better. Although the WHO is not "completely satisfied" with the current data on the two vaccines, it is expected to pass the review conditionally and will still be approved for emergency use.

01 Who evaluates vaccine data for WHO and what?

The vaccine data is evaluated by WHO's Strategic Advisory Group of Experts on Immunization (The Strategic Advisory Group of Experts on Immunization) , or SAGE for short. This agency advises WHO on vaccine technology, research and development, immunization and other issues related to health interventions.

For clinical data on vaccines, the SAGE working group examined four questions:

• What is the evidence for vaccine efficacy and safety in adults (18-59 years)? What is the evidence for the use of
• in older populations?
• What is the evidence for the efficacy and safety of vaccines in people with underlying medical conditions? How credible is the
• evidence?

These questions mainly involve three groups of people (adults aged 18-59, people over 60 years old, people with underlying diseases) , evaluating the efficacy and safety data of vaccines, and there is no horizontal comparison Efficacy and safety of different vaccines.

On April 29 and May 3, the SAGE working group evaluated the inactivated new crown vaccines of Sinopharm Beisheng Institute and Kexing respectively. The evaluation results are as follows:

Based on the evaluation reports, WHO believes that the two vaccines prevent adulthood The evidence for the efficacy of human infection with the virus is highly credible, and the evidence for safety data is moderately credible. For the elderly and people with co-morbidities, WHO considers that the quality of the evidence for the safety of the two vaccines is very low (Chinese medicine vaccine) or less than (Kexing vaccine) .

Sinopharm has two inactivated vaccines, one is Beisheng Institute and the other is Wuhan Institute.What WHO is currently evaluating is Sinopharm Beisheng Institute Vaccine (BBIBP-CorV) . The vaccine was conditionally approved by the China Food and Drug Administration on December 31, 2020, and has been approved in 45 countries or regions. It is suitable for adults over 18 years old, and the dose for emergency use has reached 65 million doses.

The Sinovac vaccine has also been approved in 32 countries or regions, suitable for adults over 18 years old, and the vaccination dose has reached 260 million doses. Such two vaccines have been used on a large scale, why is the WHO still dissatisfied, and the assessment of some aspects is actually "very low quality of evidence"? Let's take a look at the specifics.

02 Sinopharm Vaccine released clinical data for the first time, what makes WHO dissatisfied?

Prior to this, Sinopharm's vaccines have never released data, but the media has publicized that "the protection efficacy of vaccines against diseases infected by the new coronavirus is 79.34%". Because of WHO's approval, the clinical trial data of Sinopharm Beisheng's vaccine was exposed for the first time.

Judging from the results of phase 3 clinical trials conducted in the United Arab Emirates, Bahrain , Egypt , Jordan and other countries, the vaccine has a protective effect of 78.1% against diseases caused by virus infection with , which is consistent with previous news reports. numbers are similar.

But the effective rate for preventing hospitalization was only 78.7%, and the effective rate for preventing severe illness was too small (2 in placebo group, 0 in vaccine group) and could not be evaluated. The "100% prevention of severe illness" mentioned in the previous news is the simplest and crudest interpretation of the number of these 2 cases and 0 cases, and it is not scientific.

For the elderly (people over 60 years old), there were 415 people in the clinical trial, of which 209 were vaccinated and 206 belonged to the placebo group, because there was no new crown case among these 415 people, naturally it is impossible to evaluate the effectiveness sex. Based on such data, the WHO SAGE working group gave an assessment of "insufficient quality of evidence", which is also very reasonable.

If it is difficult to understand this, it may be accustomed to the simple and crude interpretation of the media. The same data can be expressed in some media as "no vaccinated person is infected", but that is not a scientific assessment. It really doesn't hurt without comparison.

Of course, in order to make up for the lack of clinical trial data, Sinopharm also provided statistical data after its listing in Bahrain. The data show that among people over 60 years old, 303 people were vaccinated, of which 65 people were infected, while 328 people were infected among 438 people who were not vaccinated, and the calculated vaccine effectiveness rate was 91% (Note : The quoted efficiency comes from the original table, I don't know how to calculate it) .

No matter how effective the data is, the data from Bahrain is only a retrospective survey data, not a formal interventional clinical trial. Therefore, the evidence is not high enough, and SAGE's conclusion that the quality of the evidence is insufficient is also reasonable.

With regard to safety data in older adults, the number of people involved in clinical trials is too small to draw any conclusions. Sinopharm provided a survey after 1.1 million doses of the vaccine were administered to the elderly over 260 years old. There were 79 adverse reaction reports received, of which 45 were considered to be related to the vaccine.

has such a data, why does SAGE still consider "very low quality of evidence"? SAGE did not give a specific answer, but it should be doubtful about the integrity of the adverse reaction tracking system.

For example, the same safety data after emergency use, the total number of doses vaccinated by adults was 5.9 million, and there were 1453 adverse reaction reports. Most of these adverse reactions , whether related to vaccines or not, are mostly mild, with a reported rate of 246 adverse reactions per million people; in contrast, among the elderly, the reported rate of adverse reactions per million people is only 72 For example, it is less than one-third of the adverse reaction rate in the general population.

For this, SAGE should be difficult to understand. Obviously, this cannot be simply interpreted as the vaccine is safer for the elderly. For people with co-morbidities, the problem is also that the number of people enrolled in clinical trials is too small. Except for the obese, each with 3000 volunteers vaccinated or placebo, the numbers of hypertension , diabetes were too small to make a reliable analysis.

In addition, in Sinopharm's clinical trials, the proportion of female volunteers is also very small, only about 15%, which also affects the reliability of the effective data.

03 260 million doses of vaccinations, why does WHO consider Sinovac's data reliable?

The data of Sinovac vaccines have been publicly reported before. In general, the SAGE working group has a higher evaluation of Sinovac vaccines, except that there is insufficient evidence for safety issues in the elderly over 60 years old and people with non-disease and health problems , there is no problem with the effectiveness of vaccines for various populations.

First of all, let’s talk about the effectiveness. Sinovac vaccines are also undergoing Phase 3 clinical trials in Brazil , Turkey, Indonesia and other places. Due to the different viral strains and age composition in different places, the protection rate of the vaccine is also different.

The most important data comes from clinical trials in Brazil. The overall efficacy of the vaccine was 50.7%, with 85 infections in the vaccine group and 168 infections in the placebo group; the effectiveness in preventing hospitalization was 100%, with 0 hospitalizations in the vaccine group and 0 in the placebo group. 10 cases were hospitalized; the efficacy in preventing severe illness was 100%, 0 cases in the vaccine group and 6 cases in the placebo group.

It should be pointed out that although the efficiency of hospitalization prevention is calculated to be 100%, because the number of cases in the control group is relatively small, only 6 to 10 cases, it may not be able to achieve such perfect protection. From the specific data, the credible range of the effectiveness of preventing hospitalization is 56.4% to 100%, and the credible range of the effectiveness of preventing severe illness is 16.9% to 100%. (Note: Other vaccines in foreign countries also have this problem in clinical data, and they all need to be interpreted with caution.)

In contrast, WHO believes that the evidence for Sinovac vaccines is more credible because it is related to the elderly and concomitant The data of patients with the disease are more complete. For the elderly over 60 years old, there were 2 infections in the vaccine group and 4 in the placebo group, and the calculated effective protection rate was 51.1%; for volunteers with concurrent diseases, the overall effectiveness was 48.9%, of which The protection rates for cardiovascular disease, hypertension, obesity, and type 12 diabetes were 39.5%, 100%, 74.9%, and 48.6%, respectively.

It should also be pointed out that in addition to obesity, the incidence of other concurrent diseases is not large, so the credible range of the protection rate is relatively large and can only be used as a reference.Based on these data, WHO has given a "moderate quality of evidence" assessment, which is also very reasonable. For the protection efficiency of the virus variant strains that everyone is more concerned about at present, Sinovac also provides clinical trial and post-market survey data.

In the clinical trial in Turkey, there is basically no mutant strain, the efficacy of Sinovac vaccine in preventing symptoms is 84%, and the efficacy in preventing hospitalization is 100%. In the post-marketing survey data of

in Chile, there are Brazilian mutant strain (P.1) , British mutant strain (B.1.1.7) , and the efficacy of Sinovac vaccine in preventing symptoms is 67%. Inpatient efficacy was 85%. In Brazil's post-marketing survey data, there is a Brazilian mutant strain (P.1) , and the efficacy of the vaccine to prevent symptoms is 50%. The mutant strain may have an impact on the protective effect of the vaccine, but the vaccine did not fail.

Regarding safety, WHO considers Sinovac vaccine to have a low risk of serious adverse events of moderate quality of evidence, and there is a certain degree of confidence that the safety is good and the risk of serious adverse events after vaccination is low.

In clinical trials, the most common adverse events were injection site pain, headache, fatigue, and myalgia. The adverse events were mostly mild/moderate, and were generally safe.After authorization for marketing, the monitoring results of safety data are as follows:

• China: According to the reports received from the 35.8 million doses of the vaccine that have been distributed, there were 49 serious adverse events, including severe allergic reactions, anaphylactic purpura, laryngeal edema , Demyelination , Cerebral hemorrhage (n≤6);
• Brazil/Indonesia: 162 serious adverse events including fever, dyspnea, Death, headache (n≤16);
• Chile: 90 serious adverse events were reported based on 3.7 million doses of vaccine distributed. The most common was clinical symptoms of severe anaphylaxis, with a reported rate of 1.7 per 100,000 doses of the vaccine, lower than the rate reported for another Covid-19 vaccine.

04 The two inactivated vaccines are not perfect, but the data is better than that of the AstraZeneca vaccine.

It should be said that the evaluation of SAGE is a relatively objective evaluation, based on the objective data provided by Sinopharm and Sinovac. This is also the evaluation of various vaccines by SAGE, which is done in this way.

For other vaccines, not every WHO has given a "high confidence in the evidence" assessment. In contrast, Sinovac's overall assessment is not as good as Moderna and Johnson & Johnson, but better than Oxford University's AstraZeneca vaccine.

With the SAGE panel's assessment, the WHO should make a decision on whether to approve both vaccines within a week. Some people read the WHO score and feel very disappointed, especially the partial score of Sinopharm's vaccine is "very low quality of evidence", and they feel that they can't pass the test. In fact, both vaccines will pass and both will be approved.So, what is the basis?

The first and most important assessment is the effectiveness and safety of the vaccine in protecting adults. The evidence for both vaccines is of high confidence and moderate quality, which is the same score as other approved vaccines.

Will the Chinese medicine vaccine be limited to 18-60 years old? It's possible, but unlikely. If you want to be more serious, no vaccine has been clinically tested in Africa , and there is no evidence that the vaccine will be effective in Africa. Should the use of vaccines be restricted in Africa?

For the elderly and people with concurrent diseases, the "very low quality of evidence" for Sinopharm vaccines does not mean that there are serious problems with safety. Is there any problem in the end, the data can be collected in the actual use process. Therefore, the WHO will not only approve the two vaccines, but also will not restrict the use of the population.

The second basis is that the WHO's approval of vaccines is not for political expression, but for the real need for vaccines to save many countries from the epidemic. At present, only 4 vaccines have been approved on the WHO's new crown vaccine emergency use list: Pfizer, Oxford University's adenovirus vector vaccine (produced by AstraZeneca, India Serum Institute, respectively), Johnson & Johnson, and Moderna.

WHO plans to purchase 2 billion doses of the new crown vaccine this year through the COVAX mechanism, half of which will be provided to developing countries. According to the progress, by the end of May, COVAX should receive 40 million doses of vaccines, but the actual number of vaccines purchased is less than a quarter.

The Serum Institute of India is the main source of COVAX. It should supply 1 billion doses this year. However, due to the impact of the tsunami of the epidemic in India, India cannot guarantee itself. The possibility of COVAX receiving the vaccine in the next few months is close to zero.

Johnson & Johnson agreed to provide 200 million doses of the vaccine to COVAX in 2021; in January this year, Pfizer Germany's BioNTech signed a contract with COVAX to provide 40 million doses of the vaccine this year; on May 3, Moderna agreed to provide 35 million doses this year. doses of vaccines; even if these vaccines are delivered on schedule, they will fall far short of COVAX’s needs. Therefore, for the two Chinese vaccines, the WHO's assessment is realistic and the demand is real.

htmlOn May 4, the European Union said it would begin rolling approvals for Sinovac's vaccine. In addition to Moderna, the new crown vaccines approved by the EU and WHO come from international giant pharmaceutical companies such as Pfizer, Johnson & Johnson, and AstraZeneca.

If it can be approved by the EU and WHO, it will be a milestone event for Chinese vaccine companies.