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Harvard: the new crown may break out in a circle. America needs social alienation until 2022

via:CnBeta     time:2020/4/19 9:32:26     readed:217

The epidemic hasn't subsided, the economy is dying, and President trump this week made a big move to "restart the United States" as soon as possible. But according to a new study from the Harvard School of public health, less effective "one-off" social alienation measures can lead to a long-term peak of the new crown epidemic.

The study, based on modeling analysis, concluded that until 2022, the United States may have been required to perform "intermittent" social estrangement interventions, unless there is a significant improvement in intensive care, or specific drugs, vaccines available.

According to the latest statistics released by Johns Hopkins University in the United States, as of 16:30 on April 18, the cumulative number of newly diagnosed cases in the United States rose to 726645, with a cumulative death rate of 37938. In the past 24 hours ,34,476 new diagnoses and 1943 new deaths have been reported in the United States.

The study was published in the top academic journal Science on April 14 local time. The corresponding authors are Marc lipsitch, Professor of epidemiology, Harvard University, and yonatan h. grad, Professor of immunology and infectious diseases, Harvard University.

At present, people urgently need to know what the transmission trend of new coronavirus might be in the future, the authors said. Based on the seasonal, immune and cross immune data of OC43 and hku1, the researchers constructed the transmission model of the new coronavirus. Researchers expect the new coronavirus to break out again this winter after this pandemic.

To measure the success of social alienation measures, the key indicator is whether local intensive care capacity can avoid "runs" under the impact of the epidemic. To avoid this, the US may still need long-term or intermittent social alienation interventions by 2022. Other measures, including expanding intensive care capacity and effective treatment methods, will increase the success rate of intermittent alienation measures and accelerate the acquisition of immunity in the population.

The researchers suggest that there is an urgent need for a longitudinal serological survey to determine the extent and duration of sars-cov-2 immunization. Even if it is eliminated obviously, we should continue to monitor the dynamics of sars-cov-2, because the new crown outbreak may occur again later in 2024.

The main conclusions of the study also include:

1. Although sars-cov-2 may show seasonal differences, it can spread at any time of the year;

2. If the immunity of convalescent patients to sars-cov-2 is not permanent: the epidemic caused by the virus is likely to enter the regular cycle;

3. if the SARS-CoV-2 transmission has a high seasonal change, it can lead to the decrease of peak incidence in the late stage of the initial pandemic, but the intensity of repeated outbreaks in winter is high;

4. If the immunity to sars-cov-2 is permanent: the virus may disappear for five years or longer after causing a major epidemic;

5. If the immunity to sars-cov-2 lasts only 2 years, the low cross immunity of other β - coronaviruses to sars-cov-2 may make sars-cov-2 disappear on the surface, but it will come back several years later.

The researchers also said that various schemes were proposed through the model to predict the possible spread of sars-cov-2 under specific assumptions. Considering the possible economic burden of continuous social alienation intervention, the researchers do not take any position on the advisability of these situations, but the researchers note that if the effect of social alienation intervention is not good and / or the duration is not long enough, it may cause a catastrophic burden on the medical system. The model will have to be tailored to local conditions and updated when more accurate data is available. Longitudinal serological studies are urgently needed to determine the degree and duration of immunity to sars-cov-2, and epidemiological surveillance should be carried out in the next few years to predict the possibility of recurrence.

Appendix: research methods

Experience in Italy, the United States and so on shows that no matter how rich the medical resources, the impact of the new crown outbreak may still encounter shortages. In the absence of specific drugs, national interventions include, inter alia, tracking contacts, isolating and increasing social distance. the intensity, duration, and urgency required for these emergency responses will depend on how the current pandemic develops and the subsequent transmission dynamics of the new coronavirus. In the initial pandemic wave, many countries have taken measures to distance themselves from social distance, and some are phasing out infectious diseases after achieving adequate control. However, researchers say intermittent social alienation policies may be needed to reduce the likelihood of a relapse. At the beginning of the new coronavirus outbreak, some analysis said that the outcome of the new coronavirus may follow its coronavirus "relatives" SARS-CoV—— after causing a brief, serious epidemic, through the strengthening of public health measures disappear. But it seems that this possibility is largely absent. The subsequent spread of the new coronavirus is more likely: seasonal transmission following a wave of infection that causes a global pandemic, similar to the pandemic. This is similar to the previous zoonotic human coronavirus ——HCoV-OC43—— but OC43 symptoms are mostly mild or even asymptomatic.

The pandemic and subsequent transmission dynamics of the new coronavirus will depend on these factors: the degree of seasonal variation of virus transmission, the duration of immunity, the degree of cross immunity between sars-cov-2 and other coronaviruses, and the intensity and timing of control measures.

Sars-cov-2 belongs to the β genus of coronaviruses, which also includes SARS CoV, mers CoV and two other human coronaviruses, hcov-oc43 and hcov-hku1.

SARS CoV and mers coronavirus can cause serious diseases, with a mortality rate of 9% and 36%, respectively, but their transmission is limited. Hcov-oc43 and hcov-hku1 may be asymptomatic or mild to moderate upper respiratory diseases; these human coronaviruses are considered the second most common cause of the common cold.

HCoV-OC43 and HCoV-HKU1 cause annual winter respiratory disease outbreaks in temperate regions, suggesting that winter climate and host behavior may contribute to the transmission of coronavirus, like influenza.

The immunity of hcov-oc43 and hcov-hku1 disappeared within one year, but SARS CoV infection can produce more lasting immunity. β - coronavirus can induce the immune reaction among them: SARS CoV infection can generate neutralizing antibody against hcov-oc43, and hcov-oc43 infection can also generate cross immune antibody against SARS CoV.

Most cases of sars-cov-2 have mild to moderate disease, and the incidence of severe lower respiratory tract infection is limited. The current mortality of covid-19 is estimated to be between 0.6% and 3.5%, indicating that the severity is lower than SARS CoV and mers CoV, but higher than hcov-oc43 and hcov-hku1. Compared with SARS CoV and mers coronavirus, the new coronavirus began to be highly infectious when the symptoms were light, which made the intervention based on case tracking difficult to work.

to date, intensive testing and case-based interventions have become central to disease control in some regions (e.g., singapore and hong kong, china). Many other countries are taking measures called "social alienation" or "physical alienation ", closing schools and workplaces and limiting the size of parties. these strategies aim to reduce the peak intensity of the epidemic (" flattening curve ", flatten the curve), reduce the risk of a run of health system resources, and buy time for the development of drugs and vaccines.

Assuming that the new crown's basic infection number R0 in China is between 2 and 2.5, if social alienation measures are to work, it is necessary to reduce the basic infection number by 50% - 60%, so as to suppress the epidemic. Studies have shown that through strong measures, Shenzhen has reduced the number of basic infections by 85%. However, it is not clear whether such an effect can be achieved elsewhere in the world. The latest data from Seattle shows that the number of basic infections in the region has only dropped to about 1.4, that is to say, only about 30% - 45%. In addition, social alienation measures may take several months to effectively control transmission and reduce the possibility of resurgence of the new crown.

The key indicator of the success of social alienation intervention is whether the number of cases will reach the critical care capacity of the local run. The model research and experience of the outbreak in Wuhan show that if the alienation measures are not implemented quickly or effectively enough, even in high-income countries, intensive care can be many times more than patients. Ways to alleviate the problem include increasing intensive care capacity, such as rapidly building or reusing hospital facilities, and increasing the manufacturing of ventilators. It can also reduce the burden of the health care system.

this study identifies viral, environmental, and immune factors that together determine SARS-CoV-2 transmission dynamics. researchers integrated the results into mathematical models to analyze the prospects of SARS-CoV-2 subsequent dissemination. Using the model, the researchers assessed how long and how strong it would take to control the new crown in the coming months after expanding intensive care.

Propagation dynamics of hcov-oc43 and hcov-hku1

researchers used data from the united states to simulate the spread β coronavirus in temperate regions and predicted possible dynamics of new crown outbreaks from now to 2025.

The researchers first evaluated the effects of seasonal factors, duration of immunity and cross immunity between hcov-oc43 and hcov-hku1 on virus infection. The researchers used data such as the percentage of weekly laboratory positive tests of hcov-oc43 and hcov-hku1 to estimate the incidence of coronavirus in the history of the United States and keep it within a certain proportion constant.

To quantify the change in transmission intensity over time, the researchers estimated the number of effective infections per week, defined as the average number of secondary infections caused by a single infected individual. The effective infection number of each β - coronavirus showed a seasonal pattern. The researchers limited the analysis to "seasonal" estimates based on sufficient samples, which were roughly distributed over 40 weeks across the year, 20 of which were in the second year, from October to may in the second year. For hcov-oc43 and hcov-hku1, the number of effective infections usually peaked in October to November and peaked in February to May of the following year. For the five seasons (2014-2019) included in the researchers' data, the median effective peak number of infections was 1.85 (range: 1.61-2.21) for hcov-hku1 and 1.56 (range: 1.54-1.80) for hcov-oc43, excluding outliers.

In order to quantify the effects of immunity and seasons on the transmission dynamics of β - coronavirus, the researchers used a regression model, which expressed the effective infection number of each strain (hku1 and OC43) as a baseline transmissible constant (this number is related to the basic infection number R0 and the proportion of susceptible population at the beginning of each season), and covered the susceptibility depletion caused by the same strain infection, another virus The susceptibility depletion caused by infection and unexplained seasonal transmission intensity change. These covariates account for most of the observed variability in the number of effective infections (adjusted R2: 74.3%). The estimated product effect of each of these covariates on the number of infections per week is shown below.

As expected, the depletion of susceptibility of each strain was negatively correlated with its ability to spread. The susceptibility consumption of each strain was also negatively correlated with the number of other β - coronavirus strains, which provided evidence of cross immunity. In addition, the ratio of cross immunity and self immunity of hcov-hku1 was higher than that of hcov-oc43, which indicated that hcov-oc43 had stronger cross immunity. The seasonal coefficients of each strain were quite consistent in all seasons, and there was no significant correlation between the seasonal and the seasonal incidence rate, which was consistent with the experimental results of the large reduction in immunity of these coronavirus strains within one year.

The researchers integrated these findings into a two variable ordinary differential equation (ODE) susceptibility exposure infection recovery susceptibility (SEIRS) model to describe the transmission dynamics of hcov-oc43 and hcov-hku1. The model is well suited for weekly incidence rate and estimated number of effective infections per week in HCoV-OC43 and HCoV-HKU1.

the R0 of HCoV-OC43 and HCoV-HKU1 varies between 1.7 in summer and 2.2 in winter according to the best fit model parameters. R0 peaks appear in the second week of january. consistent with the seasonality estimated from the data.

In the best fit SEIRS model, the immune duration of the two strains is about 45 weeks, and each strain can induce cross immunity to the other.

Simulating the spread of sars-cov-2

Next, the researchers integrated a third coronavirus into a dynamic transmission model to represent sars-cov-2.

Based on the best fit of other β - coronaviruses, the researchers hypothesized that the incubation period was 4.6 days and the infection period was 5 days. Cross immunity is allowed in the model, including the seasonal variation of immunity duration, maximum R0 and R0.

The researchers hypothesized that March 11, 2020 is the establishment time of the continuous transmission of the new coronavirus, which is the time point when the World Health Organization announced the outbreak of sars-cov-2 as a pandemic. In order to obtain a representative set of parameter values, the researchers measured the annual infection and peak prevalence of sars-cov-2 from now to 2025.

After a pandemic, researchers summarize your SARS-CoV-2 dynamics as follows: annual, biennial, sporadic, or virtual elimination. Overall, SARS-CoV-2 had shorter immune duration and less cross-immunity compared to other β coronavirus.

The following key points are proved by model simulation:

SARS-CoV-2 can spread at any time of the yea

In all modeling scenarios, sars-cov-2 can generate a large number of outbreaks no matter how long the establishment time is. The pattern from winter to the next spring tends to have a lower outbreak peak, while the pattern from autumn to winter may have a more serious outbreak.

If the convalescent's immunity to sars-cov-2 is not permanent: it is likely to enter the regular cycle

Like pandemic influenza, many scenarios will cause sars-cov-2 to enter a long-term cycle with other human β - coronaviruses, which may occur annually, biennially or sporadically over the next five years. Short term immunity (about 40 weeks, similar to hcov-oc43 and hcov-hku1) is conducive to the establishment of annual sars-cov-2 outbreak, while long-term immunity (two years) is conducive to the outbreak every two years.

High seasonal variations in transmission lead to a decrease in peak incidence in the late stages of the initial pandemic, but a high level of recurrent winter outbreaks

Like influenza, the seasonal variation of sars-cov-2 transmission has different manifestations in different geographical locations. For example, the R0 of summer influenza in New York decreased by about 40%, but that in Florida decreased by only 20%, which is basically consistent with the estimated R0 decline of hcov-oc43 and hcov-hku1. Assuming that the R0 of sars-cov-2 decreased by 40% in summer, the peak incidence after the first pandemic would be reduced. However, strong seasonal forcing will lead to an increase in the accumulation of susceptible individuals during the period of low transmission in summer, which will lead to repeated outbreaks and peaks in the post pandemic period.

If immunity to sars-cov-2 is permanent: the virus may disappear for five years or more after a major outbreak

Long term immunity can effectively eliminate sars-cov-2 and reduce the overall infection rate. If sars-cov-2 induces cross immunization against hcov-oc43 and hcov-hku1, the incidence of all β - coronaviruses may decrease or even disappear. If sars-cov-2 has 70% cross immunity to them, it is possible to eliminate hcov-oc43 and hcov-hku1, which is the same as the estimated level of cross immunity to hcov-hku1 induced by hcov-oc43.

If the immunity to sars-cov-2 lasts only 2 years, the low cross immunity of other β - coronaviruses to sars-cov-2 may make sars-cov-2 disappear on the surface, but it will come back several years later

Even though sars-cov-2 immunization lasted only two years, mild (30%) cross immunization of hcov-oc43 and hcov-hku1 could effectively eliminate the spread of sars-cov-2 for up to three years, and then re epidemic. As long as sars-cov-2 does not die out completely, it will last until 2024.

To illustrate this, the researchers used a maximum winter R0 of 2.2 based on the estimates of hcov-oc43 and hcov-hku1. For sars-cov-2, this is a low but reasonable estimate of the basic breeding population. Increasing R0 to 2.6 in winter will lead to more severe outbreaks.

Assessing interventions in the early stages of a pandemic

No matter what the post pandemic transmission dynamics of sars-cov-2 are, it is necessary to take urgent measures to deal with its continued epidemic.

drug therapy and vaccines may take months to years, while non-drug interventions (NPI) are the only direct means of curbing SARS-CoV-2 transmission.

In the countries where sars-cov-2 is widely spread, social isolation measures have been basically adopted. The necessary duration and intensity of these measures have yet to be determined. In order to solve this problem, the researchers adjusted the SEIRS transmission model to cover moderate / mild / asymptomatic infections (95.6% of infections), infections resulting in hospitalization but not intensive care (3.08% of infections), and infections requiring intensive care (1.32% of infections).

the researchers hypothesized that the worst-case scenario was that HCoV-OC43 and HCoV-HKU1 did not target SARS-CoV-2 cross-immunity, which made the SARS-CoV-2 model immune from the transmission dynamics of those viruses. According to the results of the transmission model fitting, the researchers assumed that the incubation period was 4.6 days and the infection period was 5 days, which was consistent with the estimates of other studies.

On the premise of inferring the seasonal variation of HCoV, the researchers set the peak (winter) R0 between 2.2 and 2.6, and allowed the summer R0 to change between 60% (relatively strong seasonality) and 100% (no seasonality) of the winter R0.

The researchers used the U.S. intensive care capacity of 0.89 free beds per 10000 adults as a benchmark for intensive care needs.

The researchers simulated the track of the epidemic based on the establishment time of the epidemic on March 11, 2020.

By reducing the R0 by a fixed ratio of 0% to 60%, the researchers simulated the effects of social alienation policies. Researchers assessed "one-off" social alienation interventions: for example, to reduce R0 by 60%, by performing social alienation within a fixed duration (up to 20 weeks) or by initiating an indefinite social alienation within two weeks of the onset of the epidemic.

The researchers also evaluated intermittent social alienation measures, which aim to set the social alienation function to "on" when the infection prevalence is higher than the threshold, and to set the social isolation function to "off" when the infection rate is lower than the second lower threshold, so as to maintain the number of patients in intensive care less than 0.89 per 10000 adults. The researchers set a threshold of "on" for 35 cases per 10000 people and "off" for 5 cases per 10000 adults.

In practice, thresholds need to be adjusted according to local epidemic dynamics and hospital capacity. Researchers conducted sensitivity analysis around these thresholds to assess how they affect the duration and frequency of interventions. The researchers also implemented a model with additional wards during the incubation period, infection period and each hospitalization period, so that the waiting time in these States is gamma distribution rather than exponential distribution. Finally, the researchers assessed the effect of doubling intensive care capacity (and associated on / off thresholds) on the frequency and overall duration of social alienation measures.

The researchers assessed the impact of "one-off" social estrangement measures with varying effectiveness and duration on the prevalence peaks and prevalence times of "have" or "no" seasonal changes.

When the spread is not affected by the season, one-off social alienation measures reduce the epidemic peak. In all cases, the new crown will be back in fashion after the simulation cancels social alienation measures. However, longer and more stringent measures of one-off social alienation are not always associated with further reductions in the size of the epidemic peak. For example, in a 20 week period of social alienation, R0 decreased by 60%, but the peak size of the secondary outbreak was almost the same as that of the uncontrolled epidemic: because the previous social alienation was very effective, there was almost no population immunity established. The biggest reduction of the peak size comes from the intensity and duration of social alienation, and the situation between the peaks is roughly the same.

Blue squares indicate the length of time to stay socially distant at one time. The solid line shows the simulated prevalence rate (corresponding to the data on the left side), the dotted line shows the number of severe patients (corresponding to the data on the right side), and the infection rate decreased by 0% (black), 20% (red), 40% (blue) and 60% (green) due to the social alienation of different colors

For the simulation with seasonal changes, whether in terms of the peak prevalence or the total number of infections, the peak of secondary outbreak after intervention may exceed the scale of the previous non intervention epidemic. Strong social alienation measures maintain a high proportion of the susceptible population, and when R0 rises in late autumn and winter, it will lead to a strong epidemic. There is no one-off intervention that can effectively keep the prevalence of critical patients below the capacity of intensive care.

Blue squares indicate the length of time to stay socially distant at one time. The solid line shows the simulated prevalence rate (corresponding to the data on the left side), the dotted line shows the number of severe patients (corresponding to the data on the right side), and the infection rate decreased by 0% (black), 20% (red), 40% (blue) and 60% (green) due to the social alienation of different colors

"Intermittent" social alienation can prevent a run on intensive care. due to the infection characteristics of the new crown itself, there is about 3 weeks interval between the beginning of social alienation and the peak demand for intensive care. As the propagation has strong seasonality, the social estrangement frequency in summer may be lower than R0 maximum in winter.

As the epidemic continues, the length of time between interval measures increases, as the accumulation of immunity in the population slows down the re outbreak of the disease. However, under the current intensive care capacity, the overall duration of sars-cov-2 epidemic may last until 2022, which requires social estrangement measures within 25% of the time (R0 = 2 in winter, seasonal prevalence) and 75% of the time (R0 = 2.6 in winter, seasonal prevalence).

In the left chart, the blue square represents the implementation time of social alienation policy, the black curve represents the number of patients (corresponding to the left data), the red curve represents the number of severe patients (corresponding to the right data), and the black horizontal solid line represents the number of patients and severe patients that medical resources can accommodate

With the improvement of intensive care ability, the population immunity can be accumulated more quickly, thus reducing the overall duration of the epidemic and the total duration of social alienation measures. However, the frequency and duration of social alienation measures are similar in the two scenarios of maintaining current intensive care capacity and expanding intensive care capacity. By the end of the epidemic in July 2022, social evacuation measures can be completely relaxed from the beginning to the middle of 2021, which still depends on the seasonal characteristics of the new crown. In addition, the study introduced a hypothetical treatment that halved the proportion of patients who needed hospitalization after infection, with the effect similar to doubling the capacity of intensive care.

discuss

The researchers studied a series of possible transmission scenarios of sars-cov-2 from now to 2025, and evaluated non drug interventions that could reduce the intensity of the current outbreak. If the immunity to sars-cov-2 weakens in a similar way to other coronaviruses, winter outbreaks may occur again in the next few years. By 2025, the total incidence rate of SARS-CoV-2 will depend mainly on the length of immunization time and to a lesser extent the cross immunity between HCoV OC43 / HKU1 and SARS-CoV-2.

The intensity of the initial pandemic fundamentally depends on the basic infection number R0 at the time of the establishment of the epidemic. If the new crown epidemic is established in autumn and the number of basic infections increases, it is possible to have a very high peak of infection: especially in countries where epidemic control is achieved by tracking contacts and quarantine in summer, or the transmission capacity of sars-cov-2 in summer does not decline as that of hcov-oc43 and hcov-hku1. A one-off social alienation measure may push the epidemic peak of sars-cov-2 to autumn, and if the transmissibility increases in winter, it may increase the burden of local intensive care resources. Intermittent social alienation may keep the demand of intensive care within a controllable threshold, but it requires extensive monitoring, so that alienation measures can be implemented at the right time, and avoid the run of intensive care capacity due to the outbreak.

New therapies, vaccines or other interventions (such as active contact tracking and Quarantine) can reduce the degree of social alienation while maintaining epidemic control. But in the absence of new therapies, vaccine interventions, surveillance and intermittent intervals may need to be maintained by 2022. This will bring a huge social and economic burden. In order to shorten the duration of sars-cov-2 epidemic and provide sufficient nursing for severe patients, it is urgent to improve the ability of severe nursing and formulate other intervention measures.

At the same time, serological surveys are needed to understand the degree and duration of immunity of the rehabilitated to the SARS-CoV-2, which will help determine the post-popular dynamics of the virus. whether for the short-term goal of effective implementation of intermittent social estrangement measures, or for long-term assessment SARS-CoV-2 another major outbreak is likely, continuous and extensive surveillance of the new crown virus is required. The new crown virus, even if it looks like it has been wiped out, could return in 2025.

Using data from Sweden, the researchers found that the spread of sars-cov-2 may be seasonal after a pandemic. Observations and model studies have found that effective social alienation as early as possible is essential to curb the spread of sars-cov-2. In the absence of new therapies and preventive measures, intermittent alienation measures may be the only way to avoid running on intensive care resources and gradually establish group immunity. The model's observations suggest that strong, one-off social alienation may actually lead to a stronger rebound in the epidemic, similar to the 1918 flu in the United States.

The researchers' research has been limited in a variety of ways, such as other human coronavirus observations from researchers with only five seasons. However, the model showed a pattern consistent with data from a Swedish hospital for 10 years.

The researchers' model only applies to temperate regions, which account for 60% of the world's population. The prediction of the scale and intensity of the outbreak can also be adjusted by further adding variables, such as "average human contact rate in different occasions and times" and "drug and non drug interventions". The dynamics of respiratory disease transmission in the tropics may be much more complex. The researchers predict that if the sars-cov-2 pandemic can be contained in temperate regions, the "seeds" that lead to the seasonal outbreak of the new crown will come from tropical regions. Because of the complexity of the epidemic dynamics of the respiratory system in the tropics and the ability to hibernate, it is impossible for any coronavirus strain to disappear completely.

Key parameters are needed to understand how the sars-cov-2 epidemic will develop. The key is serology research, through which we can know the degree of immunity, whether immunity is weakened and at what speed. In the researchers' model, the rate of immune attenuation is the key variable of the total incidence rate of SARS-CoV-2 in the next few years. Although long-term immunity will reduce the overall infection rate, it will also make the vaccine efficacy test complex and difficult to verify its effectiveness. For example, when Zika virus vaccine was developed before, the number of cases in the test was low. In their assessment of the control measures in the early stages of a pandemic, the researchers hypothesized that the immunity to sars-cov-2 infection lasted for at least two years. But if sars-cov-2 infection reduces immunity faster, social alienation measures may need to be expanded.

In addition, if serological surveys show that there are many undocumented asymptomatic infections that lead to immunity, then controlling the epidemic may require less social alienation.

Serology may also indicate whether there is cross immunity between sars-cov-2, hcov-oc43 and hcov-hku1, which may affect the post pandemic transmission of sars-cov-2. The researchers predict that this cross immunization will reduce the intensity of the sars-cov-2 outbreak, although some speculate that increased antibody dependence (ADE) caused by previous coronavirus infection may increase the sensitivity to sars-cov-2 and aggravate the severity of the infection. At present, there is little evidence to show the presence of ADE between coronaviruses, but if it does exist, it may promote the synergistic cycle of β - coronavirus strains.

In order to successfully implement intermittent social alienation policies, extensive virus testing is necessary to monitor the epidemic to understand when the epidemic threshold of social alienation measures is triggered. without such surveillance, the availability of intensive care bed resources can be used instead of prevalence, but because of the lag between social estrangement measures and the peak of intensive care demand, which may lead to frequent runs of intensive care resources, bedspace indicators are also far from optimal.

If the distribution of infectivity, latency, and length of stay follows a peak (e.g., the relationship between gamma and index), there is a greater risk that intensive care resources will be run. Measuring the distribution of these times, not just their average, will help set more effective thresholds for alienating interventions. In some cases, strong social alienation may reduce the prevalence of covid-19, enough to shift strategies to track and contain contacts, which has already happened in many parts of China. Nevertheless, countries that have achieved this level of epidemic control should be prepared for possible large-scale re infection and social isolation measures. Especially if seasonal factors lead to the increase of winter transmissibility. In addition, the winter peak of covid-19 will coincide with the peak of influenza, thus making the health care system more tense.

In conclusion, the total incidence rate of COVID-19 disease in the next 5 years will depend largely on whether it enters the normal cycle after the initial pandemic, which is mainly determined by the duration of immune response obtained after SARS-CoV-2 infection. The intensity and time of the first pandemic and subsequent outbreaks mainly depend on when sars-cov-2 is established in a year, and to some extent, on the seasonal characteristics of new coronavirus and the level of cross immunity between β - coronavirus.

Social alienation strategy can reduce the degree of stress in the health care system caused by sars-cov-2. As in South Korea and Singapore, efficient social alienation can reduce the incidence of sars-cov-2, so that the strategy based on contact tracking and isolation is effective. Less effective "one-off" social alienation measures can lead to a long-term single peak epidemic. Until 2022, measures of intermittent social alienation may be needed unless intensive care capacity is significantly improved or specific drugs and vaccines are available.

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