COVID-19 virus SARS-CoV-2
World Pandemic Overview
This brief summary is intended to provide up to date overview of the virus biology and its epidemiology, thus placing things in proper perspective. It is based solely on scientifically supported findings and modeling analyses using World Health Organization (WHO) published epidemiological data.
The SARS-CoV-2 virus is spread predominantly via inhalation of virus laden particles, through respiratory droplets exhaled by an infectious individual in close proximity, or particles being mixed within an aerosol cloud dispersed within a closed area (public transit, aircraft cabin, shopping malls, etc). Normally transmission through contact with inanimate objects (fomites) is less likely, but it may become important in closed settings like hospitals, hotels, airports, railway stations or cruise ships. Unlike the world famous deadly 1918 Strain A, Influenza (Spanish flu) pandemic, SARS-CoV-2 virus caused disease possesses some peculiarities which are radically different from any of the more deadly diseases. SARS-CoV-2 virus is more virulent (spreads quickly) on one hand, yet it produces relatively mild disease symptoms in vast majority of the infected population. However, it is exhibited in a broad clinical spectrum of courses, ranging from totally asymptomatic, very light to severe and even fatal outcomes. In majority of younger persons and persons with healthy immune response it usually produces asymptomatic form of the disease or mild unnoticeable flu like symptoms. In such cases the disease remains restricted to upper respiratory tract of a diseased individual and is successfully neutralized by healthy person's cell mediated immune response.
Our nasal mucosa of the upper respiratory tract is a niche immune site in which all antiviral responses are modulated by external factors such as temperature and humidity in addition to being the first site of the host's innate immune response to infection. Delayed or reduced host antiviral immune response is closely linked to COVID-19 severity and this includes suppressed interferon-induced cytokine expression, which is linked to viral disease symptoms32. Hence, in older persons with weaker immune response and in persons with underlying comorbidities such as lung disease, diabetes, cardiovascular disease, asthma, HIV, morbid obesity, liver or kidney disease1,3 the disease might take a much more severe course. In those cases the infection proceeds to lower respiratory tract and to the epithelial lining of alveolar spaces of patient's lungs. There it may become responsible for severe pulmonary infection and pneumonia, which frequently in combination with excessive innate immune response such as hyperinflammation can promote pronounced T-cell activation further amplifying inflammation and disease severity28. This might lead to death especially in older (>67 years of age), or otherwise immunocompromised persons. In clinical practice many instances were encountered where in weakened individuals the virus entered patient's blood circulation. In that case this coronavirus may attack virtually any organ in a body whose cells possess ACE2 receptor.
The virus exploits Angiotensin-Converting Enzyme 2 (ACE2) receptor in conjunction with the Transmembrane Serine Protease 2 (TMPRSS2) found primarily on epithelial cells in many organs. Both enzymes activate viral Spike protein on its surface cleaving the cell's ACE2 receptor permitting viral internalization within the host's tissue cells and begins to reproduce. Once inside the host cell this virus is characterized by very high rates of replication. The original wild type strain, which began the pandemic was shown to reproduce in upper respiratory tract as much as 1000 times faster than its related cousin - SARS coronavirus. This is likely possible in part by the fact that the viral RNA genome of SARS-CoV-2 virus possesses number of strong replication controlling elements. This forces its RNA-dependent polymerase devoting all its time to continuous replication. As a result the viral RNA polymerase also makes many mistakes in its replication transcript leading to high viral mutability.
Even otherwise healthy individuals exposed to very high infectious viral loads, as for example in case of some front line health care workers, during their infection may encounter severe course of the disease as their healthy immune system may become overwhelmed with excessive concentration of viral particles. Such situations are exceptional however, and normally about 80-91% of infections have been shown to exhibit only mild to moderate symptoms including sore throat, dry cough and fever2,9. According to 2021 Canadian numbers published by the Public Health Agency of Canada only about 5.3% of SARS-CoV-2 virus testing positive individuals required hospitalization. The remaining 94.7% of virus tested positive cases pass through asymptomatic, mild to moderate disease from which they successfully recover at home. We know however, that in most countries due to passive public reporting the official incidence statistic is underestimating the true number of exposures thus many more people get exposed to the virus than is officially reported. From a number of serological and population survey studies it was estimated that about ten times more people get infected than officially reported through testing. This value became generally accepted throughout the scientific literature. This reporting disparity primarily depends on the methodology of nation's sampling strategy. For example during a WHO sponsored "Solidarity II" global serologic study for COVID-19 in Kenya about 5-10% of Kenyans were found with SARS-CoV-2 virus specific antibodies while only 0.2% were confirmed to be testing positive by PCR methodology27. The 10x more exposures to PCR confirmations so far was accepted to be valid for majority of nations' health authorities relying on voluntary passive public reporting. In other words, if a person experiences only mild flu symptoms, and that is mostly the case, he does not bother presenting himself for COVID-19 testing, yet unknowingly he actually did contract the disease and already began mounting his immune response to it, however authorities do not know about him. This has extremely important implications for the estimates of every nation's epidemiological situation, which are largely underestimated and inaccurate.
Because of this underreporting it implies that in Canada, for example, only 0.5% of the coronavirus exposed population might develop symptoms severe enough to require hospitalization of which about half (0.25%) might succumb to the disease. In fact, in Canada in 2021 the COVID-19 fatality ratio (IFR) became established to be at 0.128%. This represents the true Canadian fatality rate of total exposed persons to the SARS-CoV-2 coronavirus and is termed the 'Infection Fatality Ratio' (IFR). The IFR is expected to be somewhat variable however, fluctuating together with the pathogen prevalent reproductive rate Rt (see below), population age structure, level of COVID-19 testing and reporting in addition to the nature of handling seriously and critically ill patients in clinical settings. For comparison, the WHO estimates the IFR for a trivial seasonal flu to be 0.1%.
Mounting evidence suggests that the severity of COVID-19 outcomes and the number of symptoms might be directly proportional to the initial load of inhaled viral particles. For example, in the Heinsberg study Streeck et al, 20203 have observed that 36% of infections were asymptomatic in subjects not participating in local festivities, as opposed to only 16% in those attending carnival. In this study many infections were acquired during local carnival festivities where large numbers of persons gathered together speaking loud and singing. The resulting infectious aerosol formation contained large concentrations (titer) of SARS-CoV-2 particles producing in infected individuals infection courses with more symptoms. This compares with approximately 40% or more of asymptomatic disease courses normally observed elsewhere. This majority of asymptomatic cases appear to be infected during day to day interactions in public, where the viral titer of infectious inoculum logically is much lower than during super spreading events of large gatherings of persons speaking loud and singing. In the same study the German investigators also observed that the frequency of SARS-CoV-2 virus infection did not differ significantly between age groups (persons of all ages may equally get infected) and sex. However, they also reported an interesting fact that the estimated risk of being infected by another person (secondary infection by a relative coronavirus carrier) in a multi-person household was much lower than expected 100%. It was observed to be 71% when living in two-person household, 53% in three-person household and 38% in four-person household. This observation confirmed similar findings of Li, W. et al. in China4.
We also know that documented re-infections of individuals by the same strain (variant) of the virus who once passed through the COVID-19 disease are rare. If they do occur the course of the second disease outcome is either very mild or asymptomatic (therefore rarely reported). This suggests that previously infected individuals do mount immune response despite relatively low observed seropositivity (presence of antibodies) within a population. Neutralizing antibodies (NAb), memory B-lymphocytes, and CD4+ and CD8+ memory T-cells to SARS-CoV-2 virus generated by infection, re-exposure or vaccination are key to acquisition of one's immunity. However, the magnitude of the antibody and T-cell response was observed to be discordant among individuals and is influenced by the disease severity23. Fan Wu et al. (2020)9 found titers of SARS-COV-2–specific NAbs in their study subjects varying substantially and included ~6% of patients who recovered successfully from mild COVID-19 with NAbs below detectable limit. The NAb titers in patients appeared to be associated with age. Older patients had significantly higher titers of NAbs than younger patients in their study. They also note that age has been reported to be an important predictor of adverse disease outcomes after infection with coronavirus. The reasons for this apparent variation in humoral response are currently hotly debated in scientific literature, however it appears that in mild COVID-19 cases no permanent humoral immunity is necessary for convalescence to take place as person's immune protection is afforded by his innate and activated cell-mediated immune response. In COVID-19 patients this is observed primarily in asymptomatic and mild courses of the disease. It follows that the strength of patient's humoral response, hence his antibody titer within his blood stream proportionately increases with the disease severity and the number of symptoms displayed. Since vast majority of COVID-19 disease courses is asymptomatic or mild (80-91%) the level of seropositivity within a population is expected to reflect this low number of severe outcomes accordingly.
In addition, after a year of raging pandemic population seropositivity in many severely affected countries like Spain and Italy remained low and generally below 20%24,25. For most US states it remained below 10% and in a number of states below 1%. In the US it was rarely observed to reach over 20%, only later dropping again back to below 20% level (New York)26. A Kenyan "Solidarity II" global serologic study for COVID-19 carried out during the first pandemic wave in that country (May-September 2020) provides a further insight into serologic dynamics elicited by the SARS-CoV-2 virus during this pandemic. During this study the seropositivity in Kenyan population was found to be between 5 to 10% and varied between 9 to 50% in different population groups. It was shown to be lowest in general population increasing substantially in health care workers and truck drivers in large cities. Not surprisingly it was highest in large urban centers like Nairobi and Mombassa dropping down at the end of the incidence wave27. Second explanation for varying and low population seropositivity observed in many countries is the timing of resulting humoral response dynamics tied to prevalent epidemiological picture within the population in question. The emergence of adaptive immunity in response to SARS-CoV-2 virus exposure occurs within the first 7 to 10 days of infection29,30,31 with secretion of serum IgM and IgA antibodies by day 5 to 7 and IgG by day 7 to 10 from the onset of symptoms. In general, serum IgM and IgA titers decline after approximately 28 days, and IgG titers peak at 49 days slowly waning to below detection limits subsequently, as the short-lived antibody producing plasmablasts (B-cells) die following the viral clearance23. It follows that in the absence of second re-infection the NAb titer normally drops with time within the population thus the observed low seropositivity merely reflects the instantaneous rate of infection incidence rather than population's immuno-protection potential.
Herd immunity threshold is defined as the proportion of individuals in a population who, having acquired natural immunity, can no longer participate in the chain of transmission. If the proportion of immunized individuals within a population surpassed this threshold, the transmission of the pathogen would be interrupted and the current outbreak would begin to extinguish. For SARS-CoV-2 virus the herd immunity threshold was initially estimated to be about 60% of the population5, however as the pandemic progressed it became apparent that this pathogen exhibits properties unlike other pathogens responsible for previous epidemics. For achieving total population resilience to COVID-19 much higher exposures to the coronavirus by the population will be required.
The Figure 2 shows comparison between Czech Republic and Sweden of epidemiology profile between March 1, 2020 and February 16, 2021. For Czech Republic notice in particular the steep run up of COVID-19 incidence to the first peak of the second wave on November 1, 2020. On November 1, 2020 only 31% of Czech population became exposed to the coronavirus and began forming their immune response to it. This steep peak was subsequently followed by an equally steep crash in incidence likely due to localized depletion of vulnerable subjects (see below). Regardless of the maintenance of strict public health intervention measures by the Czech government, shortly the first peak was followed by a second peak on January 10, 2021. By that time already 78% of Czechs became exposed to the disease and began mounting their immune response to the coronavirus. However, both Czech peaks were caused by two genetically different variants of the virus resulting in two diametrically distinct disease presentations. Presumably the gained immunity against the first strain could not at the time completely neutralize the subsequent strain.
The Table 1 below is based on start of
incidence fluctuations in selected countries. It summarizes the first dates
of achieved localized herd immunity together with the estimated percentage
of population exposure to the COVID-19 pathogen.
Table 1 - Start of wave 2 epidemiological oscillations in selected
countries indicating the first date of reaching global immunity threshold.
The achievement of herd immunity might be spatially localized and depends
on many population characteristics as much as on the nature of the pathogen.
At the onset of the COVID-19 pandemic a number
of countries contemplated relying on the development of natural herd immunity
in their populations to fight the pandemic rather than introducing strict
social distancing measures. UK initially mulled this approach. In the sequel
of escalating deaths however, UK abandoned this strategy. Sweden avoided
the use of severe social distancing measures altogether. It severely strained
its health care system in the process, nevertheless eventually managed
to minimize severe social and economic impacts stemming from harsh social
distancing measures. Today, Sweden is not in any worse position than other
countries which relied on drastic restrictions and lock downs (Fig.2).
At the onset of the first wave of the pandemic vast majority of the
world's populations was still immunologically vulnerable having no defenses
against SARS-CoV-2 coronavirus what so ever. Passing through this second
wave we are finding ourselves with majority of human populations around
the globe, but especially in North America and Europe already exposed to
at least one strain of SARS-CoV-2 virus and immune. In all nations nearing
the population's herd immunity threshold can be well visualized from the
difference in epidemiological profiles of the first and second pandemic
waves. The earlier, wave 1 is exhibited by shallow profile easily flattened
by the implementation non-pharmaceutical public health measures (Fig.1).
The latter, wave 2 entered wild oscillations characterized by accompanying
steep rises, sharp peaks, and steep falls in incidence fluctuating in relatively
short succession. This can be explained by the virus hitting more and more
individuals who have already previously been exposed to the virus and acquired
natural immune defenses to it. It likely indicates the progress of herd
immunity within the countries presented here. This progress would also
be expected to be accompanied with a gradual shift from community transmission
to isolated clusters of cases. In Canada then, the advancement of population
herd immunity can further be seen in consistent decrease in COVID-19 hospitalizations
throughout the epidemic (Table 2).
Table 2 - Consistently dropping hospitalizations in Canada on
selected dates of the pandemic further provides the evidence of the progress
of herd immunity through Canadian population.
Table 3 - summary of COVID-19 pandemic in Canada as of November 28, 2020 listing total cumulative number of cases to date as reported in ref.6. CFR-Case Fatality Rate is a number of deaths related to COVID-19 confirmed cases. IFR-Infection Fatality Rate stands for total number of death in relation to total number of infected individuals. *Total infected and therefore immunized (see discussion below for explanation).
Note: The definition of a "case" is rather subjective. It is
any individual testing +ve for the presence of SARS-CoV-2 virus RNA using
RT-PCR methodology regardless whether the individual develops any symptoms
of illness or not. RT-PCR is a rather sensitive methodology. It can detect
the presence of live SARS-CoV-2 viral genome (RNA) and its non-viable fragments
in the swab sample, or in any tissue.
According to Canadian breakdown of the incidence
of COVID-19 outbreaks in different settings of our society, it is reported
that out of total of nine settings, the long term care facilities (senior
residences) such as Québec CHSLDs and schools experienced the highest
proportions of outbreaks6. They did, however, it is predominantly
institutions like CHSLDs and schools that are subject to extensive scrutiny
by public health officials and to periodic monitoring through testing,
therefore they are likely to be over represented in the total sampling
effort. It is therefore necessary interpreting daily numbers and publicized
updates on the pandemic with caution. In addition, relying on the frequently
reported numbers obtained from clinical setting (number of hospitalized
cases, number of patients in ICUs) is an underestimation of the extent
of the pandemic on one hand, and an overestimation of the seriousness of
the disease on the other since only the very ill individuals requiring
hospitalization are recorded by the system. Many of the 80-91% of asymptomatic
and mild COVID-19 cases fall out of the picture. Unfortunately relevant
and reliable COVID-19 epidemiological studies are rare.
In the USA racial/ethnic disparities in the effect of SARS-CoV-2 virus on clinical outcomes of children of black, hispanic and asian descent were noted. Currently it is believed that these disparities are primarily of cultural and socioeconomic nature rather than genetic, therefore they will not be discussed here.
With the reference to the recognition that children are unlikely vectors to SARS-CoV-2 virus and that their infection burden is relatively light, many authors have openly questioned the value of school closures, which have been massively implemented throughout the globe during the first wave of the pandemic. They point out that the limited benefits of school closures to the disease transmission control do not outweigh the long term impacts and adversities such measures might have on lost education opportunities, physical and psychological health and well-being of children in addition to imposing increased stress burden on working parents12,13,14,17,18. There appears to be some acknowledgment of this fact on the part of the Québec Government as Premier Legault permitted our schools to remain open during the second wave of Québec epidemic.
These drastic social distancing measures come at a cost however, very high cost. They are inevitably linked to economic destruction, enormous stress and psychological traumas imposed on citizens through isolation resulting in many forms of social disharmony, possibly even in increase of suicides in addition to resulting loss of education opportunities for children and youth, and enormous hardships imposed on country's population by reduction of access to, or even complete closure or elimination of essential services. Unlike the obvious and frequently publicized numbers from the hospital ICUs the silent hardships and suffering of vast majority of citizens of countries enforcing such measures have largely gone unnoticed and unreported. The costs, though often undocumented, are heavy. Number of US authors began describing only a proportion of these costs as "excess deaths" in the US, i.e. deaths linked to COVID-19 pandemic and its intervention measures, yet not being a direct result of the disease (Bauchner H and Fontarosa PB, 202021, Woolf SH et al., 202022). These authors however, focus only on easily quantifiable deaths in the United States. They cannot document the shattered lives, relationships, livelihoods and artificially induced starvation of millions around the globe. At the beginning of the pandemic WHO apparently was aware of this, and in its Epidemiology Report #50, appropriately cautioned the governments against taking disproportionate measures as part of their non-pharmaceutical interventions:
"WHO reiterates that measures that restrict the movement of people during this outbreak should be proportionate to the public health risk, short in duration and reviewed regularly as more information about the virus, the disease epidemiology and clinical characteristics becomes available."
As the COVID-19 pandemic progressed through the first wave, with time it became clear that SARS-CoV-2 virus was not as dangerous as initially feared. Nevertheless despite of the clear recognition by the scientific community that in 80-91% of the population COVID-19 produces only mild or asymptomatic courses, in reality in Canadian provinces like Québec, and possibly others, only numbers of cases, numbers of patients in ICU and numbers of daily deaths continued to be reported through mainstream media and on public transit electronic billboards rooting irrational fears in general public. The harsh measures continued being repeatedly enforced and the above cautionary note of WHO have largely fallen on deaf ears of many misinformed and ignorant Canadian politicians who apparently sought their own political gain and popularity with fearful public rather than scientific guidance. For over a year now they have repeatedly subjected Canadians to harsh, sometimes, I do not hesitate using the word oppressive restrictions to control a disease, which is mild or asymptomatic for majority of our population. As pointed out earlier, according to the Public Health Agency of Canada, by January 23 Canada recorded 743058 confirmed positive cases of which only 39819 (5.3%), required hospitalization. In other words, total of 94.7% of official COVID-19 cases in Canada were mild or asymptomatic! This however does not include the estimated ten times more individuals (i.e. ~7430500 of Canadians) who, like myself, were by January 23 exposed to the virus yet because of mild or asymptomatic course of their COVID-19, or thinking it was just another seasonal flu chose not to be tested. It follows that in Canada only about 0.5% of COVID-19 infected individuals require hospitalization. In other words 99.5% of Canadians exposed to the coronavirus pass through the COVID-19 disease either completely asymptomatic or predominantly with mild symptoms. Canadians showing moderate symptoms still successfully recover from their disease at home. At the same time however, this same large number of coronavirus exposed individuals play an exceedingly important role in formation of nations' global (herd) immunity, as through their exposure to the disease they will start mounting their own immune response to the SARS-CoV-2 virus. This may be thought of as a natural free and safe vaccination program.
Therefore besides the fact that the present observed
trend of fluctuating and dropping incidence elsewhere clearly is unrelated
to announced and implemented government measures we know that humoral immune
response (formation of antibodies) is only one out of three effective body's
defenses against invading pathogens. Regrettably, often overlooked and
in mainstream media rarely mentioned innate and cell-mediated immunity
have always played a vital role in the first line of defense against viral
pathogens and thus in individual's recovery from any respiratory viral
disease such as seasonal Influenza or other seasonal coronaviral flu. In
addition, after over a year of fully established world pandemic we know
that SARS-CoV-2 virus infections are predominantly mild or asymptomatic
in children. In children humoral immunity is weaker than in adults, yet
it is adults, not children who predominantly spread COVID-19. It is all
three types of natural immunity that play an essential role in formation
of acquired natural global (herd) immunity at the population level. In
the two mentioned well known pandemics it was this natural herd immunity
that broke the infection chain in both pandemics and not any governments'
artificial vaccination program.
The Canadian vaccination program began on December 14, 2020. By December 27, 2020 ~5393000 Canadians have already been exposed to COVID-19 infection. Substantially delayed by the Canadian NPIs, through acquisition of their natural herd immunity by August 1, 2021 in Canada ~14290000 individuals have already begun forming their natural immune response to COVID-19. It is logical, and has been widely documented that most of exposures to SARS-CoV-2 virus primarily occur in dense urban centers. Yet, it is the residents of these large cities, already mostly naturally immunized through prior exposure, that are being encouraged, sometimes by the threat of implementation of “vaccine passports” coerced to undergo additional artificial vaccination. This way the Canadian vaccination program has largely focussed primarily on immune individuals within its cities.
With the administration of vaccine to individuals who have already mounted their adaptive immune response to a pathogen through their previous exposure the possibility of antibody cross binding and antigen competition is real33. Outcomes of such interactions at the molecular level were not clinically tested and are difficult to predict especially at such high virus mutation levels as we experience with SARS-CoV-2. In addition, as we know, in vast majority of asymptomatic and mild symptomatic COVID-19 outcomes recovery and virus neutralization might be accomplished without the formation of neutralizing antibodies likely due to extensive involvement of naturally robust innate and cell-mediated immune response. The potential interference of vaccine-produced monoclonal antibodies with T-Cell Receptors (TCRs) on surface of activated CD4+/CD8+ T-cells, Dendritic Cells (DC) and other Antigen Presenting Cells (APC) have never been evaluated.
In Canada with its population of 38 million inhabitants,
between December 14, 2020 and July 3, 2021, there were 18.4 million partial
vaccinations and 5.5 million full vaccinations carried out34.
During this period there were 551243 COVID-19 positive cases involving
unvaccinated individuals, 27461 cases of SARS-CoV-2 infections, which occurred
to individuals receiving one single dose of vaccine and 2811 individuals
were infected after receiving both vaccine doses (Table 4)34.
It follows that full vaccination with two doses of vaccine might not protect
against SARS-CoV-2 virus infection. The interpretation of number of infections
for vaccinated cases must be made with caution however. All 551243 of infected
unvaccinated individuals were at risk of infection throughout the entire
period between December 14, 2020 and July 3, 2021. Not so for vaccinated
individuals since they received their vaccination sometimes between these
two dates, hence the risk of exposure to SARS-CoV-2 virus for vaccinated
individuals was much shorter. It follows that the numbers of fully vaccinated,
yet not protected and infected individuals are much higher than officially
reported. Moreover, as stated above, in Canada vaccination program focuses
on very high proportion of individuals already immunized through prior
exposure to the virus. It is difficult to separate the already naturally
immunized, subsequently vaccinated individuals from the vaccinated naïve
subjects. Hence potentially this increases the number of failed vaccinations
Data: Public Health Agency of Canada34
The Failure of vaccination effectiveness against COVID-19 is not unique to Canada however. Massive vaccination efforts began during the first half of 2021 in majority of WHO member nations. So it was in the United Kingdom, a country having one of the most intensive vaccination rates on the European continent. Figure 3 shows the latest COVID-19 incidence profile for the UK:
The attainment of the populations' herd immunity during the second wave have largely been overlooked and drastic restrictions and draconian social distancing measures are still being enforced despite lack of evidence for their utility. Finally, we know that SARS-CoV-2 virus, which produces wide range of clinical outcomes causes complications in only small segment of immunocompromised members of our society just as any disease, no matter how common, would. One must then ask whether it is ethically acceptable holding the remaining 99.5% of healthy population hostage by imposing draconian oppressive measures and restrictions on the entire society, when the immunocompromised few could be effectively protected by focussed and separate social distancing measures until the society at large becomes properly immunized through natural herd immunity without additional social and economic costs imposed on healthy majority.
Literature Cited1 Monica Webb Hooper et al., 2020. COVID-19 and Racial/Ethnic Disparities. JAMA 2020; 323(24):2466
2 Bi Q, Wu Y, Mei S et al., 2020. Epidemiology and Transmission of COVID-19
in Shenzen, China: Analysis of 391 cases and 1286 of their close contacts.
Lancet Infect Dis 2020;S1473-3099(20)30287-5.
3 Hendrik Streeck et al., 2020. Infection fatality rate of SARS-CoV-2 infection in a German community with a super-spreading event. medRxiv preprint https://doi.org/10.1101/2020.05.04.20090076
4 Li W, et al. 2020. The characteristics of household transmission of COVID-19. Clin. Infect. Dis. doi:10.1093/cid/ciaa450PubMedGoogle Scholar
5 The Royal Society 2020. Reproduction number (R) and growth rate (r)
of the COVID-19 epidemic in the UK:methods of estimation, data sources,
causes of heterogeneity, and use as a guide in policy formulation.
6 Public Health Agency of Canada. Canada COVID-19 weekly epidemiological report, 22 November to 28 November 2020. Published December 4, 2020.
7 Saad B. Omer et al., 2020. Herd Immunity and Implications for SARS-CoV-2 Control. JAMA, doi:10.1001/jama.2020.20892.
8 Brock, TD & Madigan, MT, 1988. Biology of Microorganisms. Fifth ed. Prentice-Hall publ. pp. 506-507.
9 Fan Wu, et al., 2020. Evaluating the Association of Clinical Characteristics With Neutralizing Antibody Levels in Patients Who Have Recovered From Mild COVID-19 in Shanghai, China. JAMA Intern Med. 2020; 180(10):1356-1362. doi:10.1001/jamainternmed.2020.4616.
10 del Rio C. and Malani PN, 2020. COVID-19 - New Insights on a Rapidly Changing Epidemic. JAMA 2020; 323(14):1339-1340. doi:10.1001/jama.2020.3072.
11 US Centre for Disease Control. 2020. Coronavirus Disease 2019 in Children - United States, February 12 - April 2, 2020. Morbidity & Mortality Weekly Report. MMWR/April 10, 2020/ vol.69/ No. 14
12 Viner, RM et al., 2020. School closure and management practices during coronavirus outbreaks including COVID-19:a rapid systematic review. Lancet Child Adolesc Health, 2020;4:397-404.
13 Esposito, S. and Principi, N., 2020. School Closure During the Coronavirus Disease 2019 (COVID-19) Pandemic:An Effective Intervention at Global Level? JAMA Pediatr. 2020;174(10):921-922. doi:10.1001/jamapediatrics.2020.1892
14 Larcher, V and Brierley, J., 2020. Children of COVID-19:pawns, pathfinders or partners? J. Med. Ethics 2020; 46:508-509. doi:10.1136/medethics-2020-106465.
15 Patel, AB and Verma, A., 2020. Nasal ACE2 Levels and COVID-19 in Children. JAMA 2020;323(23):2386-2387. doi:10.1001/jama.2020.8946
16 Milani, GP et al., 2020 Frequency of Children vs Adults Carrying Severe Acute Respiratory Syndrome Coronavirus 2 Asymptomatically. JAMA Pediatr. doi:10.1001/jamapediatrics.2020.3595.
17 Zhang, L et al., 2020. Assessment of Mental Health of Chinese Primary
School Students Before and After School Closing and Opening During the
COVID-19 Pandemic. JAMA Netw Open 2020;3(9):e2021482.
18 Macartney, K. et al., NSW COVID-19 Schools Study Team. Transmission of SARS-CoV-2 in Australian educational settings:a prospective cohort study. Lancet Child Adolesc Health. doi:10.1016/S2352-4642(20)30251-0PubMedGoogle Scholar.
19 Viner, RM. et al., 2020. Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis. JAMA Pediatr. doi:10.1001/jamapediatrics.2020.4573.
20 Zhu, Y et al., 2020. Children are unlikely to have been the primary source of household SARS-CoV-2 infections. medRxiv Preprint. doi:10.1101/2020.03.26.20044826.
21 Bauchner H and Fontarosa PB, 2020. Excess Deaths and the Great Pandemic of 2020. JAMA.2020; 324(15):1504-1505.doi:10.1001/jama.2020.20016.
22 Woolf SH et al., 2020. Excess Deaths from COVID-19 and Other Causes, March-July 2020. JAMA.2020;324(15):1562-1564.doi:10.1001/jama.2020.19545.
23 Stephens DS and McElrath JM, 2020. COVID-19 and the Path to Immunity. JAMA.2020;324(13):1279-1281.doi:10.1001/jama.2020.16656.
24 Percivalle E et al. 2020. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Euro Surveill.2020;25(24):2001031.PubMedGoogle Scholar.
25 Pollán M et al.; ENE-COVID Study Group. 2020. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet.2020;396(10250):535-544. PubMedGoogle Scholar.
26 Bajema KL et al. 2020. Estimated SARS-CoV-2 seroprevalenc in the United States as of September 2020. JAMA Intern Med.doi:10.1001/jamainternmed.2020.7976Google Scholar.
27 WHO COVID-19 weekly epidemiological update report #30, 7 March 2021.
28 Hope JL and Bradley LM. 2021. Lessons in antiviral immunity. Science 371:464-465. doi:10.1126/science.abf6446.
29 Grifoni A et al. 2020. Targets of cell responses to SARS-CoV-2 coronavirus in Humans with COVID-19 disease and unexposed individuals. Cell 181:1489-1501.e15. doi:10.1016/j.cell.2020.05.015 PubMedGoogle Scholar
30 Suthar MS et al. 2020. Rapid generation of neutralizing antibody responses in COVID-19 patients. Cell Rep Med. 1(3):100040. doi:10.1016/j.xcrm.2020.100040 PubMedGoogle Scholar.
31 Robbiani DF et al. 2020. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature. doi:10.1038/s41586-020-2456-9 PubMedGoogle Scholar
32 Rasmussen AL and Popescu SV, 2021. SARS-CoV-2 transmission without symptoms. Science 371:1206-1207.
33 Abbas AK, Lichtman AH. and Pober JS, 1991. Cellular and Molecular Immunology. W.B. Saunders Publishers Company. ISBN 0-7216-3032-4
34 Canada COVID-19 Weekly Epidemiology Report, Week 28 (11 July to 17