Recently, a study came out purporting to be the very first successful human challenge trial of the “SARS-COV-2” pandemic or of any other pandemic for that matter. It is claimed that this study was able to use “wild-type virus” in order to infect healthy volunteers and study the early dynamics of “SARS-COV-2” infection. The authors claimed that they were able to uncover “novel” insights using this method. Of course, those who believe in the “SARS-COV-2” fairy tale have turned to this study as definitive proof that the agent identified as “SARS-COV-2” can cause illness in humans. However, does the creation of mild symptoms in half of the participants “infected” intranasally with toxic cell cultured goo actually prove the assumed-to-be-present-within-the-mix “SARS-COV-2” is pathogenic? Does this experimental set-up reflect nature or reality in any way? Can the results obtained from an admittedly small sample size within a highly controlled environment be extrapolated to the real-world? Before breaking down the study itself, let’s explore these questions and more a bit further.
What is a Challenge Trial?
According to the WHO:
“Human challenge trials are trials in which participants are intentionally challenged (whether or not they have been vaccinated) with an infectious disease organism. This challenge organism may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or no pathogenicity, or genetically modified in some manner.”
“Infectious human challenge studies involve deliberate exposure of human volunteers to infectious agents. Human challenge studies have been conducted over hundreds of years and have contributed vital scientific knowledge that has led to advances in the development of drugs and vaccines. Nevertheless, such research can appear to be in conflict with the guiding principle in medicine to do no harm. Well documented historical examples of human exposure studies would be considered unethical by current standards.”
“Animal models are often quite imprecise in reflecting human disease, and many infectious organisms against which a developer might wish to develop a vaccine are species-specific for humans. Human challenge trials may be safely and ethically performed in some cases, if properly designed and conducted. Tremendous insight into the mode of action and the potential for benefit in the relevant species – humans – may be gained from challenge trials. However, there are also limitations to what challenge trials may be able to ascertain because, like animal model challenge-protection studies, a human challenge trial represents a model system.”
As can be ascertained by the above quotes from the WHO, human challenge trials are those where healthy volunteers are exposed to a “pathogenic” agent in an attempt to “infect” them for further study. Obviously, this creates a bit of an ethical conundrum as the Hippocratic oath states that medical professionals should “first, do no harm.” Human challenge trials run counter to this as they are designed to intentionally harm the subjects. While the WHO readily admits that human challenge trials have been done for over a hundred years, they claim that how these trials were performed in the past would be considered unethical today. This excuse has become the rallying cry for carefully controlled lab-created exposures in order to establish infection rather than a more “natural” (and logical) approach of actually having healthy subjects interact with those who are considered carriers of the “virus” being studied. According to the WHO, it is more ethical to inject toxic cell cultured goo intranasally into healthy subjects rather than having them sit for long periods with a person considered to be suffering from the disease in order to see if they become infected “naturally.”
Learning From The Past
Why would the WHO take the position that the artificial infection methods used today are more ethical than the natural infection routes used in the past? Maybe it is because history has shown repeatedly that exposing individuals in various ways to the fluids of sick patients has no pathogenic effect. Take, for instance, the 1918 Rosenau Spanish flu experiments which I wrote about here:
“The experiment began with 100 volunteers from the Navy who had no history of influenza. Rosenau was the first to report on the experiments conducted at Gallops Island in November and December 1918. His first volunteers received first one strain and then several strains of Pfeiffer’s bacillus by spray and swab into their noses and throats and then into their eyes. When that procedure failed to produce disease, others were inoculated with mixtures of other organisms isolated from the throats and noses of influenza patients. Next, some volunteers received injections of blood from influenza patients. Finally, 13 of the volunteers were taken into an influenza ward and exposed to 10 influenza patients each. Each volunteer was to shake hands with each patient, to talk with him at close range, and to permit him to cough directly into his face. None of the volunteers in these experiments developed influenza. Rosenau was clearly puzzled, and he cautioned against drawing conclusions from negative results. He ended his article in JAMA with a telling acknowledgement: “We entered the outbreak with a notion that we knew the cause of the disease, and were quite sure we knew how it was transmitted from person to person. Perhaps, if we have learned anything, it is that we are not quite sure what we know about the disease.”69 (p. 313)
The research conducted at Angel Island and that continued in early 1919 in Boston broadened this research by inoculating with the Mathers streptococcus and by including a search for filter-passing agents, but it produced similar negative results. It seemed that what was acknowledged to be one of the most contagious of communicable diseases could not be transferred under experimental conditions.“
In various human challenge trials during what is considered the most infectious and deadly “virus,” of all time, not a single healthy subject was sickened when exposed to unhealthy subjects in various ways. While these Spanish flu studies alone should be compelling enough evidence destroying the infectious myth, they were not the only examples. The studies presented below are from a list compiled by Daniel Roytas at Humanley.com:
“Another set of 8 experiments were undertaken in December of 1919 by McCoy et al. in 50 men to try and prove contagion. Once again, all 8 experiments failed to prove people with influenza, or their bodily fluids cause illness. 0/50 men became sick.
In 1919, Wahl et al. conducted 3 separate experiments to infect 6 healthy men with influenza by exposing them to mucous secretions and lung tissue from sick people. 0/6 men contracted influenza in any of the three studies.
In 1920, Schmidt et al conducted two controlled experiments, exposing healthy people to the bodily fluids of sick people. Of 196 people exposed to the mucous secretions of sick people, 21 (10.7%) developed colds and three developed grippe (1.5%). In the second group, of the 84 healthy people exposed to mucous secretions of sick people, five developed grippe (5.9%) and four colds (4.7%). Of forty-three controls who had been inoculated with sterile physiological salt solutions eight (18.6%) developed colds. A higher percentage of people got sick after being exposed to saline compared to those being exposed to the “virus”.
In 1921, Williams et al. tried to experimentally infect 45 healthy men with the common cold and influenza, by exposing them to mucous secretions from sick people. 0/45 became ill.
In 1924, Robertson & Groves exposed 100 healthy individuals to the bodily secretions from 16 different people suffering from influenza. The authors concluded that 0/100 became sick as a result of being exposed to the bodily secretions.
In 1930, Dochez et al. attempted to infect a group of men experimentally with the common cold. The authors stated in their results, something that is nothing short of amazing.
“It was apparent very early that this individual was more or less unreliable and from the start it was possible to keep him in the dark regarding our procedure. He had inconspicuous symptoms after his test injection of sterile broth and no more striking results from the cold filtrate, until an assistant, on the second day after injection, inadvertently referred to this failure to contract a cold.”
That evening and night the subject reported severe symptomatology, including sneezing, cough, sore throat and stuffiness in the nose. The next morning he was told that he had been misinformed in regard to the nature of the filtrate and his symptoms subsided within the hour. It is important to note that there was an entire absence of objective pathological changes”.
In 1937 Burnet & Lush conducted an experiment exposing 200 healthy people to bodily secretions from people infected with influenza. 0/200 became sick.
In 1940, Burnet and Foley tried to experimentally infect 15 university students with influenza. The authors concluded their experiment was a failure.
It can be seen that numerous human challenge trials failed to produce disease in healthy subjects. Other examples of failed human challenge trails and the lack of human-to-human transmission of “viruses” can be found here. While the methods of using fluids directly from sick patients is disgusting, there should be no ethical concerns as no one ever became ill. There is no evidence of risk in the methods of the past that should keep these logical experiments from being conducted today. The only reason that the WHO and other organizations could have against experiments using these so-called “natural routes of infection” is because they are entirely aware that these experiments will fail to show infection every time.
Does the Artificial Reflect Reality?
One thing missing from any human challenge trial, whether new or old, is the purified/isolated particles claimed to be “viruses” being used as the inoculum. “Viruses” are always assumed to be within whatever fluid is used to inoculate volunteers. While the old experiments lacked purified and isolated particles, they were at least one step closer to realty as researchers typically used fluids and secretions directly from sick patients in attempts to infect healthy volunteers. In the modern version of human challenge trials, the “virus” is created in the lab through the cell culture process. This typically involves taking a sample from a sick human, immediately mixing it into a “viral” transport media containing various antibiotics/antifungals, fetal cow blood, “nutrients,” and other chemical additives. This mixture is then added to a cell culture, normally either a cancerous cell line or one derived from an animal. In this case, Vero cells derived from the kidneys of African green monkeys was used. While the researchers did not provide the exact recipe for their cultured soup, the methods section does provide a little clarity as to how their “virus” was created:
From the methods material:
“The SARS-COV-2 challenge virus (full formal name: SARS-CoV-2/human/GBR/484861/2020) was obtained with consent from a nose/throat swab taken from a patient in the UK with COVID-19 facilitated by the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C)4 using their study protocol [study registry ISRCTN66726260] approved by the South Central–Oxford C Research Ethics Committee in England (reference 13/SC/0149) and the Scotland A Research Ethics Committee (reference 20/SS/0028). The virus was isolated by inoculation of a qualified cGMP Vero cell line with the clinical sample. Sequence analysis showed this to be from the 20A clade of the B.1 lineage and possessed the D614G mutation. A Seed Virus Stock was then generated by a further passage on the same cGMP Vero cell line. The Seed Virus Stock was then used to manufacture the Challenge Virus in accordance with cGMP at the Zayed Centre for Research (ZCR) GMP manufacturing facility of Great Ormond Street Hospital (GOSH) and a Challenge Virus Master Virus Bank (MVB) was produced. Individual dose inoculum vials were then produced in accordance with 100 cGMP by dilution of the cGMP MVB with sucrose diluent. The challenge virus underwent quality testing performed as part of the GMP manufacturing release processes according to pre-determined specifications (including identity, infectivity and contaminant / adventitious agent tests). This included whole genome sequencing for confirmation that the GMP virus was unaltered compared with the original clinical isolate. The sequence of the challenge virus has been deposited in Genbank (Accession number OM294022). In the UK, since they are not medicinal products, challenge viruses are not regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). However, the challenge virus was manufactured according to GMP and the supporting paperwork was reviewed by the MHRA, which confirmed that the manufacture was suitable for the challenge agent to be used in future efficacy studies of investigation medicinal products. Therefore, in future clinical trials of an investigational medicinal product, the challenge virus will be reviewed as part of the clinical trial application to the MHRA. The challenge virus was stored in a secure –80°C freezer (normal temperature range –60°C to – 90°C) until use. The SARS-CoV-2 inoculum dose (101 113 TCID50) was selected as the lowest infectious dose could be reliably quantified by viral culture.”
We can see that the mixture used is the typical cell cultured supernatant created from Vero cells. A Seed stock of “virus” was then made from further passages in Vero cells. But don’t worry, the researchers made sure to follow Good Manufacturing Practices while manufacturing their “virus.” In order to ensure trust in their product, the MHRA regulatory board, which does not review challenge “virus” as it is not considered a medicinal product, determined that it was suitable for future use based on the paperwork submitted by the researchers. Clearly, this pharmaceutically manufactured creation is several degrees removed from realty and is as far away from nature as it can possibly get. Yet somehow, injecting this Frankenstein juice into the noses of healthy subjects is more ethical than having them coughed on by someone said to have the “virus.”
In the supplement materials, we also learn how the volunteers were “infected” with this pharmaceutically-created goop:
“Subjects were housed in single occupancy, negative pressure side rooms. Participants were inoculated intranasally by pipette with 10 TCID50 of wild-type SARS-CoV-2 (100uL/naris) between both nostrils, with an initial sentinel group (n=3) followed by the remaining individuals in the cohort. Subjects remained supine (face and torso facing up) for 10 minutes followed by 20 minutes in a sitting position wearing a nose clip post-inoculation to ensure maximum contact time with the nasal and pharyngeal mucosa.”
After obtaining their GMP goop and confirming it with sequencing, the researchers intranasally injected this into healthy volunteers. Last I checked, people said to be “infected” with “SARS-COV-2” naturally were not intranasally injected and then told to wear a nose clip for 20 minutes at any point in time during their “infections.”
The researchers then used various measurements to determine that their subjects were indeed infected. These consisted of PCR tests, “viral” load estimations, antibody tests, and antigen tests. As I have covered each of these measurements in the past, I will briefly touch on them here and provide links for further information.
In this human challenge study, one was considered infected with “SARS-COV-2” by way of PCR testing, irregardless of whether they had symptoms or not. Essentially, what the researchers did was inject their GMP-created genetic material into the nasal cavities of volunteers, swabbed their noses and throats afterwards, and acted surprised when they found the genetic material in the places where it was previously squirted. Keep in mind that no PCR test has been validated and calibrated against the gold standard of purified/isolated “virus.” They are all out on EUA only and have not been approved by the FDA. At best, all PCR can do is determine if there are certain small fragments of genetic material present in a sample. Even then, these results are incredibly suspicious as PCR is prone to contamination and relies on numerous factors such as disease prevalence, the technique of the person swabbing, the amount of material obtained, the type of test used, etc. in order to be considered accurate. In reality, all results are false results.
In order to sell the idea that those who test positive are infected with a “virus,” the researchers utilized a measurement called “viral” load in order to claim how much “virus” is present within a person at a given time. This measurement relies on the Ct value generated by the PCR test in order to estimate the amount of “virus” in a given sample. It has an inverse relationship as the lower the Ct value obtained, the higher the amount of “virus” that is said to be within a sample. The higher the Ct value, the less “virus” that is present within the sample.
While this sounds good in theory, in practice the “viral” load theory falls apart for several reasons. First, the PCR tests are only authorized for qualitative measurements (i.e. positive or negative) and are not authorized for quantitative measurements (i.e. determining how much “virus” is present). Second, there are numerous factors that impact Ct values which can throw off the results such as inefficient extraction, whether or not the patient drank something, and whether the sample was subjected to high heat during transfer. Third, according to the Association of Public Heth Laboratories (APHL), respiratory specimens are not homogeneous, are challenging to standardize, and the collection process of a respiratory specimen does not lend itself to quantifying the amount of “virus” present. If that is not enough to invalidate these measurements, you can find more reasons here.
After “infection,” serum antibody measurements were performed in order to make the case that the body was responding to a “virus.” It is claimed that neutralizing antibodies and specific IgG antibodies were present at increasing levels at different weeks and that these measurements indicated that these invisible antibodies were responding to the “virus.” However, if you were to look into antibodies it becomes clear that, as with “viruses,” these particles have never been purified nor isolated from humans. Antibodies are entirely theoretical with at least five theories attempting to explain their form and function. They are regularly non-specific despite claims stating otherwise. In fact, results from research using antibodies are nearly impossible to replicate which has led to a significant reproducibility crisis in the sciences. It is well-known that the tests measuring antibodies are nowhere near accurate with fluctuating results. As the measurements themselves vary and as there is no correlation of protection known, the results are meaningless.
Lateral flow antigen tests were also utilized in order to confirm infection. These tests are said to look for a specific “viral” antigen. As with the PCR and antibody tests, antigen tests are also only out on EUA and have never been validated and calibrared against purified/isolated “virus.” They are well known to be less accurate than the other tests and commonly rank at the bottom of the testing totem pole. According to the CDC:
“Antigen tests are immunoassays that detect the presence of a specific viral antigen, which implies current viral infection. Antigen tests are currently authorized to be performed on nasopharyngeal or nasal swab specimens placed directly into the assay’s extraction buffer or reagent.”
“Antigen tests for SARS-CoV-2 are generally less sensitive than molecular test like real-time reverse transcription polymerase chain reaction (RT-PCR) and other nucleic acid amplification tests (NAATs), which detect and amplify the presence of viral nucleic acid.”
“The clinical performance of diagnostic tests largely depends on the circumstances in which they are used. Both antigen tests and NAATs perform best if the person is tested when they are symptomatic and their viral load is high. Although antigen tests have decreased sensitivity, they can also be used to monitor infection when a person has had close contact to someone with COVID-19 with specific attention to the context in which they are used.”
We can gather from the above information by the CDC that antigen tests are not as accurate as PCR, which itself is very inaccurate. This is discussed in terms of sensitivity, which is the ability of a test to detect a true positive result. While the CDC acknowledges that antigen tests are not as “accurate” as the other tests, they failed to explain how inaccurate these tests truly are. Fortunately, the American Society for Microbiology is nice enough to provide this information:
“Similar to a cascading waterfall, there are several drops in sensitivity along the way from true cases (100% “clinical sensitivity”) to the real-world performance of rapid antigen-based SARS-CoV-2 tests, which demonstrate about 50% or lower clinical sensitivity.”
In other words, these tests are at best “accurate” only 50% of the time and thus the results are utterly meaningless.
Up to the Challenge?
There is nothing about this human challenge trial that reflects reality nor how the “virus” is supposed to infect people. The results are built upon fraudulent tests and measurements that have no meaning. Presented in full below with a summary at the end is deceptive pseudoscience at its worst:
Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge
“To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.
Coronavirus disease 2019 (COVID-19) is a complex clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research into severe disease of hospitalised patients1, and many large studies leading to approval of vaccines and antivirals2–4, the global spread of SARS-CoV-2 continues and is indeed accelerating in many regions. Infections are typically mild or asymptomatic in younger people but these likely drive community transmission5 and the detailed time-course of infection and infectivity in this context has not been fully elucidated6,7. Deliberate human infection of low-risk volunteers enables the exact longitudinal measurement of viral kinetics, immunological responses, transmission dynamics and duration of infectious shedding after a fixed dose of well-characterised virus. Under these tightly controlled conditions, host factors leading to differences in clinical outcome can be tested and robustly inferred. While human infection challenge has been attempted during previous pandemics8, none have been successfully established and no recent reports of coronavirus (including SARS-CoV-2) human challenge exist.
Experimental challenge with human pathogens requires careful ethical scrutiny and regulation but can deliver unparalleled information that can inform clinical policy and refinement of infection control measures, enabling the rapid evaluation of vaccines, therapeutics, and diagnostics. Invaluable information can be obtained by such studies in small numbers of participants under highly regulated and controlled settings, leading to wider societal benefits that offset the personal risks undertaken by the volunteers9. Recognising the potential benefits of SARS-CoV-2 human challenge, the World Health Organization convened working groups early during the COVID-19 pandemic to consider the necessary ethical and practical frameworks10. The pros and cons of human infection challenge studies have been extensively reviewed elsewhere11, but the key considerations underlying these studies during an active pandemic were to balance scientific and public health benefits with ensuring any risks to study participants (known and as yet uncertain) were minimised and managed.
The unique strengths of SARS-CoV-2 human challenge are its ability to standardise the viral inoculum, study conditions and exact timing of exposure, thus controlling for factors that unavoidably confound natural infection studies. This contrasts with even the most well-controlled field trials, including household contact studies. There, the viral quasi-species, inoculum dose, timing and conditions of exposure are unknown, and contacts are only identified following diagnosis of the index case, at which time secondary exposure has almost always already occurred12, thus missing the early phase of infection. SARS-CoV-2 human challenge studies therefore fill a gap in the understanding of early factors involved in susceptibility to infection that cannot be addressed in other ways. With continuing infection and re-infection with SARS-CoV-2, controlled translational studies such as human infection challenge that inform public health strategy as well as accelerate access to more, and improved, interventions through more robust investigation of pathogenesis, correlates of protection and early proof-of-concept efficacy testing, remain a priority that justifies the ethics of this approach.
Here, we report results from the first volunteers inoculated with SARS-CoV-2 in a human challenge study, demonstrating the feasibility of deliberate infection with SARS-CoV-2, with no evidence of serious safety signals in these carefully selected healthy volunteers, and providing novel insights into the early dynamics of infection.
SARS-CoV-2 human challenge causes rapid onset of upper respiratory tract infection with high peak viral loads.
Thirty-six healthy volunteers aged 18-29 years old were enrolled according to protocol-defined inclusion/exclusion criteria. Screening included assessments for known risk factors for severe COVID-19, including co-morbidities, low or high body mass index, abnormal safety blood tests, spirometry and chest radiography (Figure 1a & Protocol). The protocol had been given a favourable opinion by the UK Health Research Authority – Ad Hoc Specialist Ethics Committee (reference: 20/UK/2001 and 20/UK/0002). Written informed consent was obtained from all volunteers prior to screening and study enrolment. The study was overseen by a Trial Steering Committee (TSC) with advice from an independent Data and Safety Monitoring Committee (DSMB). The study was discussed with the Medicines and Healthcare products Regulatory Agency; since no medicinal product was being investigated, the study was deemed not a clinical trial according to UK regulations. As such, a EudraCT number was not assigned and the clinical study was registered with clinicaltrials.gov (identifier: NCT04865237). All participants were seronegative at screening by Quotient MosaiQ antibody microarray test and had no history of SARS-CoV-2 vaccination or infection. However, two participants seroconverted between screening and inoculation, resulting in 34 individuals in the per protocol analysis.
As this human challenge model was developed during the ongoing pandemic, with no directly comparable safety data and incomplete understanding of long-term effects following COVID-19, an adaptive protocol was designed with stepwise progression to ensure maximal risk mitigation during the early stages and progression only as data on the clinical features of human SARS-CoV-2 challenge was acquired. Following extensive screening, participants were admitted to individual negative pressure rooms in an in-patient quarantine unit, with 24-hour medical monitoring and access to higher level clinical support. At admission and before inoculation, volunteers were screened for coincidental respiratory infection using the Biofire FilmArray. Initial cohorts comprised 3 sentinel individuals followed by 7 additional participants. As per protocol, these first 10 challenged participants were assigned to receive pre-emptive remdesivir once two consecutive twelve-hourly nose or throat swabs showed quantifiable SARS-CoV-2 detection by PCR, with the aim of mitigating any unexpected risk of progression to more severe disease. Following review by the DSMB and TSC, pre-emptive remdesivir was deemed unnecessary and target recruitment of a further 30 individuals under the same conditions but without remdesivir was advised. A further sentinel cohort of 3 individuals was then challenged, with no pre-emptive remdesivir given. This was followed by 3 more groups of 7, 7 and 9 individuals, following exclusion of 4 volunteers shortly before virus inoculation due to detection of other respiratory viruses. Once pre-emptive remdesivir was no longer used, clinical severity criteria (i.e. persistent fever, persistent tachycardia, persistent severe cough, greater than mild CT imaging changes or SaO2 ≤94%) were defined for triggering of rescue treatment with monoclonal antibodies (Regeneron), but no such treatment was ultimately required. Participants were quarantined for at least 14 days post-inoculation and until they met virological discharge criteria (see Online Methods), with planned follow-up for 1 year to assess for prolonged symptoms, including smell disturbance and neurological dysfunction.
All participants were inoculated with 10 TCID50 of SARS-CoV-2/human/GBR/484861/2020 (a D614G-containing pre-alpha wild-type virus; Genbank Accession number OM294022) by intranasal drops (Figure 1b). Eighteen participants (53% according to the per protocol analysis, [95% CI [35,70]) subsequently developed PCR-confirmed infection. This infection rate met the protocol-specified target of 50-70% and there was therefore no further dose escalation. Demographics between infected participants and those who remained uninfected were similar (Table 1).
In the 18 infected individuals, viral shedding by qPCR became quantifiable in throat swabs from 40 hours (median, 95% CI [40,52]) (~1.67 days) post-inoculation, significantly earlier than in the nose (p=0.0225, where initial viral quantifiable detection occurred at 58 hours (95% CI [40,76]) (~2.4 days) post-inoculation (Figure 2a & 2b). This was initially closely paralleled by viable virus measured by focus forming assay (FFA), which was also quantifiably detected earlier in the throat than in the nose (p=0.0058, Figure 2b). Viral loads (VL) increased rapidly thereafter, with qPCR peaking in the throat at 112 hours (95% CI [76,160]) (~4.7 days) post-inoculation and later at 148 hours (95% CI [112,184]) (~6.2 days) post-inoculation in the nose (Figure 2a & 2c). However, at its peak, VL was significantly higher in nasal samples at 8.87 (95% CI [8.41,9.53]) log10 copies/mL and 3.9 (95% CI [3.34,4.42]) log10 FFU/mL than in the throat at 7.65 (95% CI [7.39,8.24]) log10 copies/mL and 2.92 (95% CI [2.68,3.56]) log10 FFU/mL (p<0.0001 for qRT-PCR and p=0.0024 for FFA, Figure 2d).
In both nose and throat, viral detection continued at high levels for several days and high cumulative VLs by area under the curve (AUC) were therefore seen, particularly in the nose (median 9.03, 95% CI [8.65,9.43] copies/mL by qPCR)(Figure 2e). In all infected participants, quantifiable virus by qPCR was still present at day 14 post-inoculation which necessitated prolonged quarantine of up to 5 extra days until qPCR Ct values had fallen to <33.5 in two consecutive nasal and throat swabs (as per protocol-defined discharge criteria). At these later timepoints, VLs by qRT-PCR were more erratic, with low level qPCR positivity remaining in 15/18 (83%) at discharge. At day 28 post-inoculation 6/18 (33%) remained qPCR positive in the nose and 2/18 (11%) in the throat but by day 90 all participants were qPCR negative. Of the participants not meeting infection criteria and deemed uninfected, low level non-consecutive viral detections were observed only by qPCR in the nose of 3 participants and throat of 6 participants (Extended Figure 1a & 1b).
In contrast, viable virus was detectable by FFA for a more limited duration: 156 hours (median, 95% CI [120,192]) (6.5 days) in the nose and in the throat for 150 hours (95% CI [132,180]) (6.25 days; Figure 2f). The average time post-inoculation to clearance of viable virus was 244 hours (95% CI [208, 256]) or 10.2 days from the nose and 208 hours (95% CI [172,244]) or 8.7 days from the throat (Figure 2g). VLs by qPCR and FFA were significantly correlated in both nose and throat (Extended Figure 3a & 3b). Although there was a striking degree of concordance between the shape and magnitude of individuals’ VL curves (Figure 2a) and between VLs in the nose and throat (Figure 2i), greater inter-individual variability was observed in timing of VL between nose and throat (Extended Figure 4). Despite relatively high levels of late qPCR detection, the latest that viable virus could be detected was day 12 post-inoculation in the nose and day 11 in the throat (Figure 2g). In contrast, swabs by qPCR that became undetectable in quarantine during the resolution phase first occurred at 352 hours (95% CI [340,364]) (~14.6 days) in the nose and 340 hours (95% CI [304,352]) (~14.7 days) in the throat although some later continued to fluctuate around the limits of quantification and detection (Figure 2h).
Of the first 10 participants prospectively assigned to receive pre-emptive remdesivir on PCR-confirmed infection, 6 became infected. No apparent differences were seen in VL by qPCR (Extended Figure 2a) or FFA (Extended Figure 2b) between remdesivir-treated and untreated infected individuals and cumulative virus (AUC) was similar (Extended Figure 2c). While there was an apparent trend towards lower mean nasal VL during the treatment period and delayed VL peak in the 6 remdesivir-treated individuals (Extended Figure 2d), this was not observed in the throat, primarily driven by one individual and was not statistically significant. With no significant differences between remdesivir-treated and untreated participants, infected individuals were therefore analysed together.
Serum neutralising antibodies are mounted rapidly following SARS-CoV-2 challenge infection
The rapid onset of infection was reflected in serum antibody responses. No increase in serum antibodies by microneutralisation or anti-spike protein IgG ELISA was observed in those deemed uninfected, even where isolated viral detections had occurred, except for one participant who acquired natural COVID-19 after discharge from quarantine (Figure 3a & 3b). In contrast, serum antibodies were generated in all infected participants with neutralising antibody titres of 425 (median, IQR 269) at 14 days post-inoculation and a further rise to 863.5 (IQR 403) at 28 days (Figure 3a). A slower rise was seen in spike protein-binding IgG measured by ELISA, with a median increase to 192.5 (IQR 393.1) ELU/mL at day 14 followed by an increment by day 28 to 1549 (IQR 1865) ELU/mL (Figure 3b). Of note, in the two participants who seroconverted between screening and inoculation, both neutralising and S protein binding antibodies were detectable at admission to the quarantine unit on day -2 pre-inoculation. Both individuals were excluded from the per protocol infection rate analysis but remained uninfected, with no change in their serum antibody levels post-inoculation.
SARS-CoV-2 human challenge infection causes mild disease with no evidence of serious safety signals
Following infection, symptoms by self-reported diary (Supplementary Table 1) became apparent from 2-4 days post-inoculation (Figure 4a) when symptoms started diverging from challenged but uninfected individuals, who reported both fewer and milder symptoms with no consistent pattern (Figure 4a and Extended Figure 1c). Symptom scores exhibited greater variability than VLs, with inconsistent onset and peak cumulative daily scores ranging from 0 to 29. Symptoms were most frequent in the upper respiratory tract and included nasal stuffiness, rhinitis, sneezing and sore throat (Figure 4b, 4c and Extended Figure 5). Systemic symptoms of headache, muscle/joint aches, malaise and feverishness were also recorded. There was no difference in symptoms between remdesivir-treated and untreated individuals (Extended Figure 6). All symptoms were mild-to-moderate, with peak symptoms (at 112 hours post-inoculation (95% CI [88,208]) aligning closely with peak VL in the nose, which was significantly later than peak VL in the throat by FFA (88 hours, 95% CI [76,112], p=0.0114) (Figure 4d, Extended Figure 4). However, despite the temporal association between nasal VL and symptoms, there was no correlation between the amount of viral shedding by qPCR or FFA and symptom score AUC (Figure 4e & 4f).
Seven participants (39% of infected) had temperatures of >37.8°C. Otherwise there were no notable disturbances in any clinical assessments, including daily spirometry and thoracic CT scans. No serious adverse events were reported and no criteria for commencing rescue therapy were met. A total of 18 adverse events deemed probably or possibly related to virus infection were largely due to transient and non-clinically significant leukopenia and neutropenia, and mild muco-cutaneous abnormalities during the quarantine period (Table 1 and Supplementary Table 2).
SARS-CoV-2 human challenge infection commonly causes smell disturbance
To assess the degree and kinetics of smell disturbance, University of Pennsylvania Smell Identification Tests (UPSITs) were conducted. No smell disturbance was observed during quarantine in uninfected individuals (Extended Figure 1d). However, 12 infected participants (67%) reported some degree of smell disturbance. While other symptoms peaked with nasal VLs, the nadir of UPSIT scores was 6-7 days later (Figure 4a, Extended Figure 4). Complete smell loss (anosmia) occurred in 9 individuals (50%), but most experienced rapid improvement before day 28. Although at day 28 some smell disturbance was still reported by 11 participants (61%), by day 180 this number had fallen to 5. Of these, only one individual still had measurable smell impairment at 180 days post-inoculation, although this was improving both subjectively and objectively (UPSIT at baseline=31, day 11=9, day 28=11, day 90=17, day 180=23). Two of the remaining reported mild parosmia and two had mild reduction in smell subjectively (although UPSIT scores had normalised). Six individuals received smell training advice, including 2 who also received treatment with short courses of oral and intranasal steroids.
Anosmia is therefore a common feature of human SARS-CoV-2 challenge that generally onsets several days later than viral shedding and resolves quickly in most individuals. Together, these findings indicate that human SARS-CoV-2 challenge at this inoculum dose has low risk of causing severe symptoms in healthy young adults but leads to large amounts of nasopharyngeal virus even in the absence of respiratory or systemic disease.
Antigen testing by lateral flow assay is strongly associated with virus detection by quantitative culture
Lateral flow assay (LFA) rapid antigen tests are commonly used to identify potentially infectious people in the community but their usefulness in early infection is unknown. To test the performance of LFA over the entire course of infection, antigen testing was performed using the same morning nose and throat swab samples assessed for VL. None of the uninfected participants had a positive LFA test at any time, whereas all infected individuals had positive LFA for ≥2 days (Extended Figure 7). Despite earlier viral detection in the throat by other methods, median time to first detection by daily LFA tests was the same in nose and throat at 4 days (range 2-8) post-inoculation (Figure 5a). This was on average 24-48 hours after first qPCR positivity (Figure 5b) and within 24 hours of FFA (Figure 5c). Of note, in 9 of 18 infected individuals, viable virus became detectable by FFA one or more day before the first positive LFA. Towards the end of infection, the last LFA detection mainly occurred 24-72 hours after viable virus detection had ceased.
To assess the relationship between VL and probability of a positive LFA, logistic regression models were fitted using generalised estimating equations to control for repeated within-participant assessments. Log10 VL was a significant predictor (P<2×10−5) of LFA positivity with an odds ratio of 5.01 (95% CI [2.93,8.57]) when predicting LFA from FFA in nose (Figure 5e). Area under the receiver operating characteristic curves (AUROC) were high at 0.96 for nasal qPCR, and 0.89 for throat qPCR (Extended Figure 8a) but lower for FFA, particularly in the throat (AUC 0.69). To test longitudinal performance as infection progressed, the sensitivity and specificity of LFA when compared with qPCR and FFA were calculated for each day post-exposure (Figure 5f). With both tests and anatomical sites, sensitivity of LFA was limited at the beginning and end of acute illness. However, from ~4 days post-inoculation, LFA demonstrated high sensitivity as a surrogate for qPCR or FFA-positivity. Overall, LFA was highly specific although some “false positives” were observed in relation to FFA (but not qPCR).
Where asymptomatic/pre-symptomatic LFA testing programmes exist, testing is usually recommended twice weekly. To model the differential impact of LFA testing frequency that incorporate viral dynamics throughout infection, the mean proportion of VL AUC that had yet to occur (and might be responsible for transmission if undiagnosed) by the time of a first positive LFA test with testing cadences of 1-7 days was modelled. For both FFA (Figure 5g) and qPCR (Extended Figure 8b), infection would be recognised at or before >90% of the VL AUC had occurred if testing was daily. As the period between tests increased, the proportion of VL AUC declined with twice-weekly testing capturing 70-80% of virus and weekly testing still exceeding 50% if nose and throat swabs were combined. Thus, LFA positivity is strongly associated with culturable virus and therefore contagiousness and can be highly effective as a trigger for interventions to interrupt transmission.
We here report the virological and clinical results from the first SARS-CoV-2 human challenge study. With a low inoculum dose of 10 TCID50, robust viral replication was observed in 53% of seronegative participants. After an incubation period of <2 days, VLs escalated rapidly, peaking at high levels and continuing for over a week. Symptoms were present in 89% of infected individuals but, despite high VLs, were consistently mild-to-moderate, transient and predominantly confined to the upper respiratory tract. Anosmia/dysosmia was common, occurred later than other symptoms and resolved without treatment in most participants within 90 days. In those with residual smell disturbance, their sense of smell steadily improved during the follow-up period, consistent with the good long-term prognosis seen in community cases13. There was no evidence of pulmonary disease in infected participants based on clinical and radiological assessments.
The natural infectious dose of SARS-CoV-2 is unknown but based on in vitro and preclinical models, the virus is understood to be highly infectious14–16 and well-adapted to rapid and high-titre replication in human respiratory mucosa17. Early in the pandemic, a WHO Advisory Group published expert consensus guidelines recommending a starting dose of 102 TCID5010. Here, based on in vitro data of high viral replication in primary human airway epithelial cells, we started with a tenfold lower dose of 10 TCID50 (equivalent to 55 FFU) and found it sufficient to meet the 50-70% target infection rate. With prospective household contact studies having similarly shown high secondary attack rates of ~38%12, this suggests that the model can recapitulate higher exposure than naturally-acquired infection events. In contrast, experimental infections of non-human primates have used 1,000-10,000 times more virus, with intratracheal or combined upper/lower airway administration, which results in markedly different kinetics to those observed during human infection18,19. In human challenge studies with other respiratory viruses such as influenza viruses and RSV, inoculum doses are typically also much higher at 104-106 TCID50 since all volunteers have been exposed multiple times throughout life to those viruses, with pre-existing immunity reducing susceptibility and resulting in substantially lower peak viral loads at 103-104 copies/mL by PCR20,21. Thus, neither animal models nor human data from other viral infections were helpful in estimating the optimal SARS-CoV-2 inoculum dose.
Although some studies have measured the response to SARS-CoV-2 infection longitudinally in humans22–24, none can capture host features at the time of virus exposure, the early events prior to symptom onset, or the detailed course of infection that can be shown by experimental challenge. Whilst the incubation period from the estimated time of natural exposure to perceived symptom onset has previously been estimated as ~5 days25,26, this best aligns with peak symptoms and is longer than the true incubation period. With close questioning, symptoms were found to be associated with viral shedding within 2 to 4 days of inoculation but did not peak until day 4-5. Thus, virus was first detected (first in the throat, then the nose) ~2 days before peak symptoms and increased steeply to achieve a sustained peak, in many cases before peak symptoms were reached, consistent with modelling data indicating that up to 44% of transmissions occur before symptoms are noted6. Anosmia was a later symptom, potentially explained by the proposed mechanism whereby only ACE2- and TMPRSS2-expressing supporting cells rather than neurones themselves are directly infected, leading to delayed secondary olfactory dysfunction27.
Pre-emptive remdesivir was administered to the first 6 infected participants as risk mitigation during early model development as trial data had suggested efficacy in shortening time to recovery in hospitalised patients28. However, no statistically significant effect on viral load or symptoms was detectable in this small cohort. Field data have questioned the effectiveness of remdesivir in the hospitalised patient setting29 but antiviral treatment is commonly more effective early in the course of infection. This study was not designed nor powered to assess the efficacy of early treatment with remdesivir so this remains to be tested, but such prospective human challenge studies would be well placed to answer the question of antiviral efficacy, with treatment commenced at different times relative to virus exposure.
A key unresolved question for public health has been whether transmission is less likely to occur during asymptomatic/mild infection compared to more severe disease. Some studies have shown a correlation between disease severity and extent of viral shedding30,31, but others have not32. Overall, peak VLs reported in natural infection (~105-108 copies/mL) are lower than those observed in this study6,33−36 However, these are invariably sampled at the time of case ascertainment and, where longitudinal samples have been taken, these indicate that patients are already in the downward phase of the VL curve24. It is therefore likely that most samples miss the peak of viral shedding. With virus present at significantly higher titres in the nose than the throat, these data provide clear evidence that emphasises the critical importance of wearing face coverings over the nose as well as mouth. Furthermore, our data clearly show that SARS-CoV-2 viral shedding occurs at high levels irrespective of symptom severity, thus explaining the high transmissibility of this infection and emphasising that symptom severity cannot be considered a surrogate for transmission risk in this disease. This remains relevant with the widespread transmission of the Delta and Omicron variants, where antigenic divergence along with waning vaccine-induced immunity lead to VL during breakthrough infection at comparably high levels to those in seronegative individuals12,37.
Despite the relatively small sample size, limited variation between infected study participants and longitudinal analysis permits several conclusions of public health importance. Detailed viral kinetics show that some individuals still shed culturable virus at 12 days post-inoculation (i.e. up to 10 days after symptom onset) and, on average, viable virus was still detectable 10 days post-inoculation (up to 8 days after symptom onset). These data therefore support the isolation periods of 10 days post-symptom onset advocated in many guidelines to minimise onward transmission38. High levels of asymptomatic/pauci-symptomatic viral load also highlight the potential positive impact of routine asymptomatic testing programmes that attempt to diagnose infection in the community so that infection control measures such as self-isolation can be implemented to interrupt transmission. In several jurisdictions, these rely on rapid antigen tests, with recent re-analysis of cross-sectional LFA validation data having suggested that sensitivity for infectious virus may be higher than previously estimated at ~80%39. Reassuringly, longitudinal LFA data following SARS-CoV-2 challenge also strongly predicted culturable virus aside from the very earliest time-points where sensitivity was lower. In addition, LFA was highly reliable in predicting the disappearance of viable virus and therefore also underpin “test to release” strategies, which are increasingly being used to shorten the period of self-isolation. While positive LFA results were occasionally seen with negative FFA results (causing a reduction in specificity in relation to the viable virus assay), there were no false positives when comparing LFA to qPCR, implying the relatively lower sensitivity of viral culture rather than false positivity of LFA. Although some uncertainty remains in directly extrapolating these data to the community where self-swabbing and more concentrated samples may alter sensitivity, these results support their continued use for identifying those most likely to be infectious. Our modelling also suggests that this strategy remains effective even if imperfectly implemented, with routine testing as little as every 7 days able to interrupt more than half the virus still to be shed by an individual, if acted upon.
Although these first-in-human data do not preclude rare adverse events that can only be detected in larger-scale studies, our results indicate that human challenge with SARS-CoV-2 is consistent with natural infection in healthy young adults, having caused no serious unexpected consequences and therefore supporting further development and expansion. This first report focuses on safety, tolerability and virological responses, but the uniquely controlled nature of the model will also enable robust identification of host factors present at the time of inoculation and associated with protection in those individuals who resisted infection. Analysis of local and systemic immune markers (including potentially cross-reactive antibodies, T cells and soluble mediators) from this SARS-CoV-2 human challenge study that may explain these differences in susceptibility are therefore ongoing. In addition, with the feasibility of this approach having been demonstrated using a prototypic wild-type strain, further challenge studies are now underway in which previously infected and vaccinated volunteers will be challenged with escalating inoculum doses and/or viral variants to investigate the interplay between virus and host factors that influence clinical outcome. Together, these studies will thus optimise the platform for rapid evaluation of vaccines, antivirals and diagnostics by generating efficacy data early during clinical development and avoiding the uncertainties of studies that require ongoing community transmission.”
- According to the WHO, human challenge trials are trials in which participants are intentionally challenged (whether or not they have been vaccinated) with an infectious disease organism
- This challenge organism may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or no pathogenicity, or genetically modified in some manner
- Human challenge studies have been conducted over hundreds of years yet such research can appear to be in conflict with the guiding principle in medicine to do no harm
- Well documented historical examples of human exposure studies would be considered unethical by current standards
- Animal models are often quite imprecise in reflecting human disease
- There are limitations to what challenge trials may be able to ascertain because, like animal model challenge-protection studies, a human challenge trial represents a model system
- The “SARS-COV-2” challenge “virus” (full formal name: SARS-CoV-2/human/GBR/484861/2020) was obtained with consent from a nose/throat swab taken from a patient in the UK
- The “virus” was then “isolated” by inoculation of a qualified cGMP Vero cell line with the clinical sample (i.e. it is a cell cultured goo mixture of human/monkey DNA, fetal cow blood, antibiotics/antifungals, “nutrients,” and chemical additives)
- A Seed “Virus” Stock was then generated by a further passage on the same cGMP Vero cell line
- The Seed “Virus” Stock was then used to manufacture the Challenge “Virus” in accordance with cGMP at the Zayed Centre for Research (ZCR) GMP manufacturing facility of Great Ormond Street Hospital (GOSH) and a Challenge “Virus” Master “Virus” Bank (MVB) was produced
- The challenge “virus” underwent quality testing performed as part of the GMP manufacturing release processes according to pre-determined specifications (including identity, infectivity and contaminant / adventitious agent tests)
- In the UK, since they are not medicinal products, challenge “viruses” are not regulated by the Medicines and Healthcare products Regulatory Agency (MHRA)
- However, the challenge “virus” was manufactured according to GMP and the supporting paperwork was reviewed by the MHRA, which confirmed that the manufacture was suitable for the challenge agent to be used in future efficacy studies of investigation medicinal products
- In other words, trust them, it’s all legit and on the up-and-up as they followed the non-existent regulations as determined by the regulatory board that does not regulate challenge “viruses”
- Subjects were injected with the GMP goop intranasally, remained supine (face and torso facing up) for 10 minutes, followed by 20 minutes in a sitting position wearing a nose clip post-inoculation to ensure maximum contact time with the nasal and pharyngeal mucosa
- To establish a novel “SARS-CoV-2” human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a “wild-type virus” (SARS-CoV-2/human/GBR/484861/2020) intranasally
- Eighteen (~53%) became infected, with “viral” load (VL) rising steeply and peaking at ~5 days post-inoculation
- There were no serious adverse events
- Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation
- Anosmia/dysosmia developed more gradually in 12 (67%) participants
- No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection
- In other words, even those who had no symptoms had high levels of “virus” detected
- Infections are typically mild or asymptomatic in younger people but these likely drive community transmission and the detailed time-course of infection and infectivity in this context has not been fully elucidated
- Under these tightly controlled conditions, host factors leading to differences in clinical outcome can be tested and robustly inferred (i.e. guess, speculate, or surmise)
- While human infection challenge has been attempted during previous pandemics, none have been successfully established and no recent reports of “coronavirus” (including “SARS-CoV-2”) human challenge exist
- Invaluable information can be obtained by such studies in small numbers of participants under highly regulated and controlled settings, leading to wider societal benefits that offset the personal risks undertaken by the volunteers
- The key considerations underlying these studies during an active pandemic were to balance scientific and public health benefits with ensuring any risks to study participants (known and as yet uncertain) were minimised and managed
- The unique strengths of “SARS-CoV-2” human challenge are its ability to standardise the “viral” inoculum, study conditions and exact timing of exposure, thus controlling for factors that unavoidably confound natural infection studies (why would they want to study a “virus” naturally when it can be studied artificially?)
- The authors state that they provided novel insights into the early dynamics of infection (while “novel” can mean new, it can also mean an invented prose narrative that is usually long and complex and deals especially with human experience through a usually connected sequence of events…so.take your pick…?)
- Screening included assessments for known risk factors for severe “COVID-19,” including co-morbidities, low or high body mass index, abnormal safety blood tests, spirometry and chest radiography (in other words, a very reflective sample of society…)
- This human challenge model was developed during the ongoing pandemic, with no directly comparable safety data and incomplete understanding of long-term effects following “COVID-19”
- As per protocol, these first 10 challenged participants were assigned to receive pre-emptive remdesivir once two consecutive twelve-hourly nose or throat swabs showed quantifiable “SARS-CoV-2” detection by PCR, with the aim of mitigating any unexpected risk of progression to more severe disease
- Following review by the DSMB and TSC, pre-emptive remdesivir was deemed unnecessary and target recruitment of a further 30 individuals under the same conditions but without remdesivir was advised
- A further sentinel cohort of 3 individuals was then challenged, with no pre-emptive remdesivir given
- Once pre-emptive remdesivir was no longer used, clinical severity criteria (i.e. persistent fever, persistent tachycardia, persistent severe cough, greater than mild CT imaging changes or SaO2 ≤94%) were defined for triggering of rescue treatment with monoclonal antibodies (Regeneron), but no such treatment was ultimately required
- In other words, Remdesivir was pre-emptively given based only on PCR results but not symptoms/clinical dianosis and once it was deemed unnecessary, monoclonal antibodies were on standby based on symptoms/clinical diagnosis but was never given
- Pre-emptive Remdesivir should disqualify the first 10 challenge subjects if they developed symptoms which could have been due to side effects of the drug
- Eighteen participants (53% according to the per protocol analysis, [95% CI [35,70]) subsequently developed PCR-confirmed infection (i.e. they found the cultured genetic material shoved in the noses of 18 subjects…shocking…)
- In all infected participants, quantifiable “virus” by qPCR was still present at day 14 post-inoculation which necessitated prolonged quarantine of up to 5 extra days until qPCR Ct values had fallen to <33.5 in two consecutive nasal and throat swabs (as per protocol-defined discharge criteria)
- Of the participants not meeting infection criteria and deemed uninfected, low level non-consecutive “viral” detections were observed only by qPCR in the nose of 3 participants and throat of 6 participants
- Of the first 10 participants prospectively assigned to receive pre-emptive remdesivir on PCR-confirmed infection, 6 became infected
- With no significant differences between remdesivir-treated and untreated participants, infected individuals were therefore analysed together
- No increase in serum antibodies by microneutralisation or anti-spike protein IgG ELISA was observed in those deemed uninfected, even where isolated “viral” detections had occurred, except for one participant who acquired natural “COVID-19” after discharge from quarantine (wait…they detected “virus” but considered them uninfected?)
- Following infection, symptoms by self-reported diary became apparent from 2-4 days post-inoculation when symptoms started diverging from challenged but uninfected individuals, who reported both fewer and milder symptoms with no consistent pattern (wait…the uninfected had symptoms?)
- Symptoms were most frequent in the upper respiratory tract and included nasal stuffiness, rhinitis, sneezing and sore throat (which shouldn’t be surprising considered the toxic goo was administered INTRANASALLY)
- All symptoms were mild-to-moderate
- Despite the temporal association between nasal VL and symptoms, there was no correlation between the amount of “viral” shedding by qPCR or FFA and symptom score AUC
- Seven participants (39% of infected) had temperatures of >37.8°C
- Otherwise there were no notable disturbances in any clinical assessments, including daily spirometry and thoracic CT scans
- No serious adverse events were reported and no criteria for commencing rescue therapy were met
- A total of 18 adverse events deemed probably or possibly related to “virus” infection were largely due to transient and non-clinically significant leukopenia and neutropenia, and mild muco-cutaneous abnormalities during the quarantine period
- 12 infected participants (67%) reported some degree of smell disturbance (and disturbed smell is somehow unexpected after injecting toxic goo in noses?)
- Anosmia is therefore a common feature of human “SARS-CoV-2” challenge that generally onsets several days later than “viral” shedding and resolves quickly in most individuals
- Together, these findings indicate that human “SARS-CoV-2” challenge at this inoculum dose has low risk of causing severe symptoms in healthy young adults but leads to large amounts of nasopharyngeal “virus’ even in the absence of respiratory or systemic disease (i.e. they find large amounts of “virus” genetic material in the nose without any disease)
- Lateral flow assay (LFA) rapid antigen tests are commonly used to identify potentially infectious people in the community but their usefulness in early infection is unknown
- To assess the relationship between VL and probability of a positive LFA, logistic regression models were fitted using generalised estimating equations to control for repeated within-participant assessments
- To test longitudinal performance as infection progressed, the sensitivity and specificity of LFA when compared with qPCR and FFA were calculated for each day post-exposure and with both tests and anatomical sites, sensitivity (i.e. ability to designate an individual with disease as positive) of LFA was limited at the beginning and end of acute illness
- However, from ~4 days post-inoculation, LFA demonstrated high sensitivity as a surrogate for qPCR or FFA-positivity
- Overall, LFA was highly specific although some “false positives” were observed in relation to FFA (but not qPCR)
- With a low inoculum dose of 10 TCID50, robust “viral” replication was observed in 53% of seronegative participants (in other words, they again admit it was genetic material, not disease observed)
- Symptoms were present in 89% of infected individuals but, despite high “viral” loads, were consistently mild-to-moderate, transient (lasting a short time) and predominantly confined to the upper respiratory tract
- There was no evidence of pulmonary disease in infected participants based on clinical and radiological assessments
- The natural infectious dose of “SARS-CoV-2” is unknown but based on in vitro and preclinical models, the “virus” is understood to be highly infectious and well-adapted to rapid and high-titre replication in human respiratory mucosa
- In other words, what they “know” about the “virus” is based on lab created data and animal models
- Early in the pandemic, a WHO Advisory Group published expert consensus guidelines recommending a starting dose of 10^2 TCIDv50^10
- Based on in vitro (in the lab) data of high “viral” replication in primary human airway epithelial cells, they started with a tenfold lower dose of 10^2 TCIDv50 (equivalent to 55 FFU) and found it sufficient to meet the 50-70% target infection rate (keep in mind, infection means finding genetic material, not disease)
- With prospective household contact studies having similarly shown high secondary attack rates of ~38%, this suggests that the model can recapitulate higher exposure than naturally-acquired infection events (i.e. the model does not reflect nature)
- In contrast, experimental infections of non-human primates have used 1,000-10,000 times more “virus,” with intratracheal or combined upper/lower airway administration, which results in markedly different kinetics to those observed during human infection (thus the animal data would be meaningless to humans)
- With close questioning, (as in leading questioning…?) symptoms were found to be associated with “viral” shedding within 2 to 4 days of inoculation but did not peak until day 4-5 (keep in mind, the reporting of symptoms is entirely subjective and could be influenced by the psychological impact of constant swab testing and belief in infection)
- Pre-emptive remdesivir was administered to the first 6 infected participants as risk mitigation during early model development as trial data had suggested efficacy in shortening time to recovery in hospitalised patients
- Overall, peak “viral loads” (VLs) reported in natural infection (~105-108 copies/mL) are lower than those observed in this study
- “Virus” was present at significantly higher titres in the nose than the throat (might this have something to do with the INTRANASAL inoculation…?)
- The authors state that their data clearly show that “SARS-CoV-2 viral” shedding occurs at high levels irrespective of symptom severity, thus explaining the high transmissibility of this infection and emphasising that symptom severity cannot be considered a surrogate for transmission risk in this disease
- In other words, they found lots of genetic material in the nose of half of those who had the cultured goo squirted down their nasal passages but no severe disease
- The authors admit to their relatively small sample size
- Positive LFA results were occasionally seen with negative FFA results causing a reduction in specificity in relation to the viable “virus” assay
- Uncertainty remains in directly extrapolating these data to the community where self-swabbing and more concentrated samples may alter sensitivity (i.e. the lab data does not reflect real-world data)
- These first-in-human data do not preclude rare adverse events that can only be detected in larger-scale studies
The first “successful” human challenge trial was only able to “infect” half of the participants with “infection” based primarily on PCR tests finding the genetic material in the areas it was injected into. Only mild-to-moderate symptoms were self-reported by 16 of the 18 volunteers “infected.” There was no quantitative correlation noted between supposed “viral” load and symptoms, with high “viral” loads even in asymptomatic infection. The first 10 volunteers were given pre-emptive Remdesivir if they tested positive without any symptoms. The symptoms reported among those ten volunteers could easily have been caused by the side effects from the treatment thus disqualifying those results. Low level “viral” material was found in the nose of 3 uninfected volunteers and in the throat of 6 uninfected volunteers. Although they were considered milder, the uninfected also reported symptoms.
The researchers concluded that their “novel” findings indicated that human “SARS-CoV-2” challenge was low risk of causing severe symptoms in healthy young adults but led to large amounts of nasopharyngeal “virus’ even in the absence of respiratory or systemic disease. In other words, infection was not clinical but rather diagnostic which is the primary problem we have faced throughout this entire Testing Pandemic.
Had the researchers followed the examples from the past, they would have taken the fluids from sick patients and attempted to aerosolize them in the face of the healthy while they breathed in. They would have had the healthy individuals sit with and talk to unhealthy individuals for certain periods of time to see if a “virus” was transferred from person-to-person. They would have had the sick cough and sneeze on the healthy to see if these actions led to infection. They would have explored every possible means of what is considered “natural infection.”
There is nothing natural nor ethical about the methods used during this human challenge trial. The creation of the GMP goop is not purified/isolated “virus.” The intranasal inoculation of the lab concoction is not a natural mode of infection. The controlled environment does not reflect real world settings. The various tests used to collect the data have never been validated and calibrated against the gold standard and are highly faulty as well as inaccurate. The trial consisted of a small sample size with no controls performed. The researchers admitted that uncertainty remained in directly extrapolating their data to the community. There is no reason to conclude that the “novel” information gathered from this trial can tell us anything about a “virus” at all unless the researchers are using the term to describe their long-winded science fiction.