# 新冠病毒疫苗三期试验中期揭盲条件及保护率研究Study on Uncovering Blindness Requirements and Protection Rate in the Midterm of Phase III Clinical Trial of COVID-19 Vaccine

Abstract: By extending the concept of vaccine protection rate, the concepts of protective measures protection rate, vaccine protection rate under the background of protective measures, and the comprehensive protection rate of vaccines (protection rate under the combined action of protective measures and vaccines) were established. According to the list comparison of the protective measures protection rate of the countries where the phase III trial of COVID-19 vaccine was conducted, the protective measures protection rate which was conducted had an important impact on the trial progress. In order to speed up the progress, it is suggested that the phase III trial should be carried out in the countries where the protective measures protection rate is low as far as possible. It is pointed out that the results of vaccine protection rate are not comparable in the context of different protective measures, especially in countries with high protection rate, there is a problem of reliability in the calculation of vaccine protection rate. There will even be failure to meet the uncovering blindness requirements of the midterm of current phase III trial. We demonstrate the comparability of the protection rate under the combined action of protective measures and vaccines, and that the relative error of the protection rate has the ability of anti-interference to the vaccine protection rate under the protective measures. Therefore, we suggest that the protection rate be used as an index to evaluate the effectiveness of the vaccine. According to the nature of the suggested evaluation indexes, we suggest that the uncovering blindness requirements in the midterm of phase III should be modified as follows: the trial period is limited to three months, and it can be ended earlier when the total number of patients meets the statistical requirements. We have also established a measure of whether the vaccine’s protection is significant, by which we can determine the need for vaccination in a particular location.

Abstract:

1. 引言

2. 疫苗保护率及其延伸定义

$\begin{array}{c}疫苗保护率=\left(对照组发病率-接种组发病率\right)/对照组发病率\ast 100%\\ =\left(1-接种组发病率/对照组发病率\right)\ast 100%\end{array}$ (1)

1) 防护措施保护率(bp)

${b}_{p}=1-\frac{{r}_{p}}{{r}_{c/n}}$ (2)

2) 无防护措施下的疫苗保护率(bv/n)

${b}_{v/n}=1-\frac{{r}_{v/n}}{{r}_{c/n}}$ (3)

3) 防护措施下的疫苗保护率(bv/p)

${b}_{v/p}=1-\frac{{r}_{v/p}}{{r}_{c/p}}$ (4)

4) 疫苗综合保护率(bv+p)

${b}_{v+p}=1-\frac{{r}_{v/p}}{{r}_{c/n}}$ (5)

3. 疫苗三期试验所在国防护措施保护率计算及与进度关系初步分析

Table 1. Protection rate of protection measures in phase III clinical trial of COVID-19 vaccine

4. 目前疫苗三期试验得到的保护率bv/p缺乏可比性和中期揭盲要求存在不合理性

4.1. 不同防护措施下，疫苗保护率bv/p缺乏可比性

1) 同一种疫苗在不同防护措施保护率的国家，因为试验周期的不同造成疫苗保护率bv/p缺乏可比性。

${m}_{c/n}=m×{r}_{c/n}$ (6)

${m}_{v/n}\stackrel{\left(3\right)}{=}{m}_{c/n}×\left(1-{b}_{v/n}\right)$ (7)

${m}_{c/p}\stackrel{\left(2\right)}{=}{m}_{c/n}×\left(1-{b}_{p}\right)$ (8)

${m}_{v/p}\stackrel{\left(4\right)}{=}{m}_{c/p}×\left(1-{b}_{v/p}\right)$ (9)

Table 2. Number of infected persons following three-month trials in countries with different protection rates of protection measures

2) 在同一个国家，采用防护措施前后得到的疫苗保护率bv/n和bv/p缺乏可比性。

4.2. 在防护措施保护率bp较高情况下，计算疫苗保护率bv/p存在可靠性问题

${b}_{v/p}=\frac{{m}_{c/p}-{m}_{v/p}}{{m}_{c/p}}$ (10)

${b}_{v/p}+\Delta {b}_{v/p}=\frac{\left({m}_{c/p}+\Delta {m}_{c/p}\right)-\left({m}_{v/p}+\Delta {m}_{v/p}\right)}{{m}_{c/p}+\Delta {m}_{c/p}}$

$\Delta {b}_{v/p}=\frac{1-{b}_{v/p}}{1+\frac{\Delta {m}_{c/p}}{{m}_{c/p}}}\left(\frac{\Delta {m}_{c/p}}{{m}_{c/p}}-\frac{\Delta {m}_{v/p}}{{m}_{v/p}}\right)$ (11)

$\Delta {b}_{v/p}=-\frac{1}{{m}_{c/p}+\Delta {m}_{c/p}}\left(\Delta {m}_{v/p}-\left(1-{b}_{v/p}\right)\Delta {m}_{c/p}\right)$ (12)

$\Delta {b}_{v/p}\approx -\frac{1}{{m}_{c/p}+\Delta {m}_{c/p}}\Delta {m}_{v/p}$${b}_{v/p}\to 1$

4.3. 达到统计学意义的发病人数才可以中期揭盲存在合理性问题

${m}_{c/p}+{m}_{v/p}={m}_{0}$

$m{r}_{c/n}\left(1-{b}_{p}\right)\left(2-{b}_{v/p}\right)\frac{T}{3}={m}_{0}$

5. 疫苗综合保护率研究

$\begin{array}{c}{b}_{v+p}=1-\left(1-{b}_{p}\right)\left(1-{b}_{v/p}\right)\\ ={b}_{p}+{b}_{v/p}\left(1-{b}_{p}\right)\\ ={b}_{v/p}+{b}_{p}\left(1-{b}_{v/p}\right)\end{array}$ (13)

${b}_{p}\le {b}_{v+p}\le 1$${b}_{v/p}\le {b}_{v+p}\le 1$ (14)

${b}_{v+p}+\Delta {b}_{v+p}={b}_{p}+\Delta {b}_{p}+\left({b}_{v/p}+\Delta {b}_{v/p}\right)\left[1-\left({b}_{p}+\Delta {b}_{p}\right)\right]$

$\Delta {b}_{v+p}=\Delta {b}_{p}\left[1-\left({b}_{v/p}+\Delta {b}_{v/p}\right)\right]+\Delta {b}_{v/p}\left(1-{b}_{p}\right)$

$0\le {b}_{v/p}+\Delta {b}_{v/p}\le 1$

$|\Delta {b}_{v+p}|\le |\Delta {b}_{p}|+|\Delta {b}_{v/p}|\left(1-{b}_{p}\right)$ (15)

$\frac{|\Delta {b}_{v+p}|}{{b}_{v+p}}\le \frac{|\Delta {b}_{p}|}{{b}_{p}}+\frac{|\Delta {b}_{v/p}|}{{b}_{v/p}}\left(1-{b}_{p}\right)$ (16)

$\frac{|\Delta {b}_{v+p}|}{{b}_{v+p}}\le 0.1\frac{|\Delta {b}_{v/p}|}{{b}_{v/p}}$

6. 新冠病毒疫苗三期试验合理的中期揭盲条件及疫苗具有显著性作用指标研究

7. 结论和建议

1) 首先尽量选择防护措施不足的国家进行疫苗三期试验。

2) 三期揭盲的条件设定为：试验以三个月为限，在总发病人数达到统计学要求时提前结束。

3) 评价过程分两步。

Table 3. I and bv+p vaccines indicators for the five enterprises that are currently progressing rapidly

[1] 医学名词审定委员会全科医学与社区卫生名词审定分委员会. 全科医学与社区卫生名词[M]. 北京: 科学出版社, 2004.

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