ACCURACY & DURABILITY - LATERAL FLOW - SARS-CoV-2 RAPID ANTIGEN

SARS-CoV-2 rapid Antigen test

OROPHARYNGEAL

RESULTS IN 20 MINUTES

Asymptomatic Identified

Specificity

Sensitivity

CT values to 30

SARS-CoV-2 rapid Antigen test

ANTERIOR NARES

RESULTS IN 20 MINUTES

=> ongoing worldwide clinical trials performed on over 500 subjects from 2020-2021

=> 0% False Positives accomplished with 390 negative patient samples

=> 0% Cross Reactivity accomplished with 44 common viruses including SARS-CoV-1, interfering substances and bacteria

=> Withstanding Extreme Heat & Freezing Environments

=> Extended shelf-life

Manufacturing COVID-19 Lateral Flow Rapid Tests in the USA with the highest sensitivity and durability possible.

Backed by Robust Clinical Studies

Little is known about coronavirus disease 2019 (COVID-19) dynamics and patterns in the African continent (Olyainka et al., 2021).  Evaluation of 224 SARS-CoV-2 genome sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) sequenced early on in the novel COVID-19 (nCoV-2019) outbreak, showed that 69 of the sequences were from Africa.  Mutation classification based on country and region, demonstrates that once a mutation is imported into Africa, subsequent mutations are a certainty.

Investigation of the evolution and genetic diversity of SARS-CoV-2 in Africa reveal, a year ago, a rapidly diversifying SARS-CoV-2 population (Motayo et al., 2020, in one year (Mar 1, 2020 – Jan 7, 2021), led to five (5) different lineages that dominated during distinct periods of the pandemic. Of the five lineages, B.1.1 (n = 518 sequences, 9.91% of the diversity) circulated continuously throughout the sampling year, representing an ongoing clade of active mutation. B.1.1 is prevalent in Europe, is a dominant lineage in Asia, and is most prevalent in North America (USA and Canada) [Olayinka et al., 2021]. This represents widespread high order prevalence across 4 of the largest continents.  Thus, the emergence of B.1.1.529 (Omicron), a branch off B.1.1 that was  first detected in Botswana, November 9, 2021, now a variant of concern because of its partial immune escape mutation profile (European Centre for Disease Prevention and Control, 2021), highlights the importance of reducing the reproductive number, R, i.e. transmissibility of detrimental mutations that may originate and/or circulate through Africa by ensuring resources are on-hand for the treatment of remote villages and communities at a population scale. Because B.1.1.529 (Omicron) shows signs of escaping current vaccines, it represents an inflection point in the virus’ threat profile, bringing Africa sharply into focus in terms of how critical and vital it is to secure Africa, where Omicron can reservoir in asymptomatic hosts, against Omicron and SARS-CoV-2/COVID-19, in general, for Europe, Asia and North America to survive SARS-CoV-2’s evolution.

Africa is the world’s least vaccinated continent and the origin of a number of SARS-CoV-2 variants. Africa is also the continent with the most immunocompromised population and multiple adverse socioeconomic factors and barriers to equitable healthcare access. For example, the current locus of activity of the Omicron variant in Africa is in South Africa, the origin of two variants: the Beta variant and C.1.2. South Africa is a deeply unequal society.[1] Only 16% of South Africa’s population has access to medical aid,[2] with most of its population relying on the public healthcare sector that is under resourced. In addition, the South African healthcare system carries a significant burden of tuberculosis (TB), HIV, and HIV/TB co-infection, with millions of the population on immunosuppressant drugs as well as others who are HIV positive, but not receiving treatment for HIV.[3]  This raises concerns that those with these immunosuppressing co-morbidities are more susceptible to SARS-CoV-2 infections and have a higher risk of developing severe COVID-19 disease.[4]  In this regard, South Africa has the world’s largest HIV epidemic, with an estimated 8.2 million people infected. While most take antiretrovirals, many do not and neighboring countries also have very high HIV infection rates.

Throughout the continent, the burden of diseases is higher than most parts of the world. Diseases like TB are rampant and extreme poverty means that millions are in ill health and have little ability to fight off infections. The longer COVID-19 persists in its host, the longer it sheds, replicates/reproduces, the greater probability it will mutate.  In fact, “there is good evidence that prolonged infection in immunocompromised individuals is one mechanism for the emergence” of COVID-19 variants, such as Omicron, said Tulio de Oliveira, a bioinformatics and genetics professor who heads Next Generation Sequencing (NGS) institutions at 2 South African universities[5], including University of KwaZulu-Natal in Durban.  In fact, it raises the question if “HIV patients whose infections are not controlled with medication could ‘become a factory of variants for the whole world” according to de Oliveira.[6]

24.1 The Cost of One (1) False Positive

Certainly, false-positive COVID-19 test results impose significant costs and hidden problems–categorically, both macro- (globally) and micro- (individually) [Surkova et al., 2020]. As costly as it may be personally to the individual, the cost to society is quantified in Du et al. (2021) as US $3,835.62/2 weeks (14 days) of life lost according to their multiscale model, which describes SARS-CoV-2 transmission both at the population scale (macro) and daily viral load dynamics at the individual scale (micro). This cost assumes daily testing at US $5/test combined with a 2-week self-quarantine period because of the false-positive test result [Du et al., 2021]. US $5 is designated as the price point per unit by a set of agreements between

global organizations at the highest levels[1] to make available 120 million LFAs to 2nd and 3rd

world countries[2] (note: as far as the USA is concerned, this cost basis underestimates current wholesale prices for antigen-based Rapid Diagnostic Tests (RDTs) in the market by about ½ [Mike Membrino, NAD, personal communication]), which may be why it is frequently chosen as the cost per antigen-based RDT in published models (Atkeson et al., 2020; Ricks et al., 2021 and WHO, 2020b). Comparably, Ricks et al. (2021) models the cost of isolation/day in a hospital setting to be US $50-350/day (an average of $200/day) [Nagarajan R, 2020; Netcare Hospitals, 2019 and Reddy et al., 2020] for a duration of isolation of 10 days (Ricks et al., 2021).  At the upper limit of US $350/day x 10 days, this amounts to US $3,500/10 days of life lost, which compares favorably to the modeled estimate of the multiscale model.

If anything, the cost basis is a lower bounds, since there are many COVID-19 edge cases that cost the employer, including but not limited to: 1. despite vaccination, a subgroup suffer “breakthrough” infections; 2. despite getting infected, a subgroup experience re-infection(s); 3. post-infection, a subgroup, called COVID-19long haulers” continue to suffer, on an ongoing basis, COVID-19-associated sign(s) and symptom(s), requiring leave(s) of absence or “sick days off”, costing the employer lost productivity and opportunity cost(s) and 4. for the rest, the reality that COVID-19, like the flu, will be an ongoing, recurring threat, constantly mutating into new variant(s) that may resist/escape vaccination and/or require new vaccination, treatment, and serial testing.

Across 173 datasets and 124 studies, a total of 61 different antigen-based RDTs (48 LFAs with visual readout) were evaluated (Brummer et al., 2021). Across all meta-analyzed studies (124), when antigen-based RDTs were performed according to manufacturer’s recommendations, they showed a diagnostic sensitivity of 76.3% (95% CI: 73.1% to 79.2%) with SD Biosensor’s STANDARD Q nasal (80.2% diagnostic sensitivity [95% CI 70.3% to 87.4%]) performing best [The PLoS Medicine Staff, 2021]. In stark contrast, a Cochrane review (Dinnes et al., 2021), across 48 studies, evaluating 58 antigen tests, using data from instructions for use (IFU)-compliant tests in symptomatic participants, contradicted Brummer et al. (2021), reporting summary diagnostic sensitivities ranging from 34.1% (95% CI: 29.7% to 38.8%) to 88.1% (95% CI: 84.2% to 91.1%), but with SD Biosensor STANDARD Q also performing best (Dinnes et al., 2021). Of note, average specificities were high in symptomatic and asymptomatic participants, and for most brands demonstrated an overall summary diagnostic specificity of 99.6% (95% CI:99.0% to 99.8%).

At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), the global standards for LFAs for the 2nd and 3rd world countries (120 million units projected to be distributed), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results (average: 1 in 8 [16.67%]) will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed (false negative)

Contrast this with NAD’s AN offering with a diagnostic sensitivity of 95.6% and a diagnostic specificity of 100% (see Results, preceding).  By eliminating false positives, companies will save an estimated US $3,500 – $3,835.62/employee saved from isolation. Considering NAD’s low COGS for its LFA, a 1% investment by an employer (US $3.50 – $3.83/test kit) can return a 100x return in potential cost savings without the liability and risk exposure of 99% of the LFA test kits on the market.

Moreover, its temperature stability (2-month stability at a sustained 100 with a combined 15-month shelf life at room temperature) [IHL/SD, personal communication] and robust response to POC stress (300% excess drops of reagent by operator error) make it the most accurate and durable LFA in the market today. Effective therapy is only possible when a disease is diagnosed quickly and reliably (Urusov et al., 2019). The key characteristics of an ideal IVD are that it is both accurate, durable, and low cost.  In the case of the NAD Lateral Flow Nucleo-Option(™) COVID-19 Rapid Antigen Test, there is no need to tradeoff any of the 3 features.

24.2 Global Population Public Health Protocol at Scale

Current real-time estimates of the effective Reproduction Rate (Re) [Achaiah et al., 2020] for COVID-19 worldwide curve-fit at: 1.06 (Nov 17, 2021; 7:57 am EST, model dashboard) using a Kalman filter (Arroyo-Marioli et al., 2021)–indicating slow (and low) transmission worldwide, on average.

Figure 5, Real-Time Estimates of the global Re

Such forecasting is critical (Achaiah et al., 2020) because Du’s multiscale modeling (Du et al., 2021) shows a cost-effective testing strategy under low transmission (Re of 1-2) scenarios of monthly testing of a population followed by 1 week isolation rather than the current 2 weeks (Du et al., 2021) and that expanded surveillance testing is more likely to be cost-effective than the current status-quo testing if the price per test is less than US $75 across any and all transmission rates modeled. Further modeling favors serial testing with LFAs only and Bayesian statistical analysis to obviate the need for a time-consuming confirmation by PCR (Ferretti et al., 2021). Frequent LFA with an economical, accurate and durable antigen-based RDT, such as the NAD Lateral Flow Nucleo-Option™ COVID-19 Rapid Antigen Test is needed now for COVID-19 population health testing at scale as we approach COVID-19 global endgame scenarios (Kofman et al., 2021).

In conjunction with serial screening, we have to be extremely discriminatory in the selection process of RDTs and the process of RT-PCR has to be converted away from its use as a screening tool and more as an active false positive diagnostic alert tool, if anything, at the very least, after a 2nd RDT to backstop discrepancies between RDTs and for QA/QC as we shift towards mandated testing (reflected by the Biden Mandate) and pervasive testing and contact tracing. It is now the LFIA/LFA doing agile discovery for us on our front lines and in the trenches.

25       References

[1] Statistics South Africa, “Inequality Trends in South Africa: A Multidimensional Diagnostic of Inequality” (accessed Apr 13, 2020).

[2] Council for Medical Schemes, Annual Report 2015/2016.

[3] The estimated overall HIV prevalence

[4] Academy of Science in South Africa, ASSAf Statement on the Implications of the Novel Coronavirus (SARS-CoV-2; COVID-19) in South Africa.

[5] Bloomberg, “HIV and Covid-19 in Africa” (accessed Nov 27, 2021).

[6] L.A. Times, “As COVID-19 collides with HIV/AIDS, the pandemic may be taking an ominous turn”, story published 3/6/21.

 Achaiah NC, Subbarajasetty SB, Shetty RM (2020) “R0 and Re of COVID-19: Can We Predict When the Pandemic Outbreak will be Contained?” Indian J Crit Care Med 24(11):1125–1127.

Arroyo-Marioli F, Bullano F, Kucinskas S and Rondón-Moreno C (2021) “Tracking  of COVID-19: A new real-time estimation using the Kalman filter” PLoS ONE 16(1): e0244474.

 Atkeson A, Droste MC, Mina M and Stock JH (2020) “Economic benefits of COVID-19 screening tests”, NBER Working Paper 28031, National Bureau of Economic Research (NBER), Cambridge, MA, USA

Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M (2020), “Presumed asymptomatic carrier transmission of COVID-19” JAMA 323(14):1406-7.

 Brummer LE et al. (2021) “Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: a living systematic review and meta-analysis”, PLoS Med 18(8): e1003735.

Cheng MP, Papenburg J, Desjardins M et al. (2020), “Diagnostic testing for severe acute respiratory syndrome-related coronavirus-2: a narrative review”, Ann Intern Med 172(11):726-734.

Dinnes J, Deeks JJ, Berhane S, Taylor M, Adriano A, Davenport C, Dittrich S, Emperador D, Takwoingi Y, Cunningham J,Beese S, Domen J, Dretzke J, Ferrante di Ruffano L, Harris IM, Price MJ, Taylor-Phillips S, Hoo- L, Leeflang MMG, McInnes MDF, Spijker R and Van den Bruel A (Cochrane COVID-19 Diagnostic Test Accuracy Group) [2021] “Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection”,  Cochrane Database of Systematic Reviews Issue 3, Art. No.: CD013705.

Du Z, Pandey A, Bai Y, Fitzpatrick MC, Chinazzi M et al. (2021) “Comparative cost-effectiveness of SARS-CoV-2 testing strategies in the USA: a modelling study”, Lancet Public Health 6: e184-91.

Ferretti L, Wymant C, Nurtay A, Zhao L, Hinch R, Bonsall D, Kendall M, Masel J, Bell J, Hopkins S, Kilpatrick AM, Peto T, Abeler-Dörner L, Fraser C (2021) “Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts”, medRxiv 2021.08.06.21261725.

FIND, Rapid diagnostic tests for COVID-19, webpage accessed July 1, 2021 – November, 2021.

Fwoloshi et al. (2021) “Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 among healthcare workers—Zambia, July 2020”, Clinical Infectious Diseases 73: e1321.

Goldstein N and Burstyn I (2020) “On the importance of early testing even when imperfect in a pandemic such as COVID-19”, Preprint ver. 4, Preprint doi: 10.31219/osf.io/9pz4d.

  Kofman A, Kantor R and Adashi EY (2021), “Potential COVID-19 endgame scenarios: eradication, elimination, co-habitation or conflagration?” JAMA 326(4):303-304.

 Kostoulas P, Eusebi P and Hartnack S (2021), “Diagnostic accuracy estimates for COVID-19 real-time polymerase chain reaction and lateral flow immunoassay tests with Bayesian Latent-Class Models” Am J Epidemiol 190(8):1689-1695.

Kruger LJ, Gaeddert M, Tobian F, Lainati F, Gottschalk C, Klein J, Schnitzler P, Krausslich HG, Nikolai O, Lindner AK, Mockenhaupt FP, Seybold J, Corman VM, Drosten C, Pollock NR, Knorr B, Welker A, de Vos M, Sacks JA, Denkinger CM et al. (2021) “The Abbott PanBio WHO emergency use listed, rapid, antigen-detecting point-of-care diagnostic test for SARS-CoV-2—Evaluation of the accuracy and ease-of-use” PLoS One 16(5): e0247918.

Lee VJ, Chiew CJ and Khong WX (2020) “Interrupting transmission of COVID-19: lessons from containment efforts in Singapore”, Journal of Travel Medicine 27(3): taaa039.

Li Q, Guan X, Wu P et al. (2020a) “Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia”, New England Journal of Medicine 382: 1199-1207.

Li R, Pei S, Chen B, Song Y, Zhang T, Yang W and Shaman, J (2020b) “Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2)” Science 368(6490): 489-493.

Mizumoto K, Kagaya K and Chowell G (2020) “Early epidemiological assessment of the transmission potential and virulence of coronavirus disease 2019 (COVID-19) in Wuhan City, China, January–February, 2020” BMC Medicine 18, 217.

 Nagarajan R (2020) “Hospital cost capped, but COVID can cripple 80% of families”, The Times of India (online).

Netcare Hospitals (2019), “Netcare Tariffs” (online).

 Rabaan AA et al. (2021) “Viral dynamics and real-time RT-PCR Ct values correlation with disease severity in COVID-19” Diagnostics 11: 1091.

Reddy KP, Shebi, FM, Foote JHA, Harling G, Scott JA, Panella C et al. (2021) “Cost-effectiveness of public health strategies for COVID-19 epidemic control in South Africa: a microstimulation modelling study”, Lancet Global Health 9(2): E120-E129.

 Representatives of the Commission services, the European for Disease Prevention and Control (ECDC) et al. (2020) “Current performance of COVID-19 test methods and devices and proposed performance criteria”, a working document of Commission Services, European Commission, pp. 1-30 with Annexes 1-3 (“Commercial devices” [1], “Scientific Literature” [2] and “Search on validation studies” [3]).

 Ricks S, Kendall EA, Dowdy DW, Sacks JA, Schumacher SG and Arinaminpathy N (2021) “Quantifying the potential value of antigen-detection rapid diagnostic tests for COVID-19: a modelling analysis”, BMC Medicine 19: 75.

Rimmer A (2020) “COVID-19: BMA calls for rapid testing and appropriate protective equipment for doctors” British Medical Journal (Online); London 368: m1099.

Saah AJ and Hoover DR (1997) “ ‘Sensitivity’ and ‘specificity’ reconsidered: the meaning of these terms in analytical and diagnostic settings” Ann Intern Med 126(1): 91-4 (not free, purchase required).

Slezak P and Waczulikova I (2011) “Reproducibility and Repeatability” Physiological Research 60: 203-205, letter to the editor, comment on: Jira M, Zavodna E, Novakova Z, Fiser B, Hozikova N (2010) “Reproducibility of blood pressure and inter-beat interval variability in man” Physiol Res 59(Suppl 1): S113-S121.

Sun Q, Qiu H, Huang M and Yang Y (2020) “Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province” Annals of Intensive Care 10(1): 33.

Surkova E, Nikolayevskyy V, Drobniewski F. (2020) “False-positive COVID-19 results: hidden problems and costs” Lancet Respir Med 8(12):1167-1168.

The PLOS Medicine Staff (2021) “Correction: Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: A living systematic review and meta-analysis”, PLoS Med 18(10): e1003825.

Tuite AR, Bogoch II, Sherbo R et al. (2020) “Estimation of coronavirus disease 2019 (COVID-19) burden and potential for international dissemination of infection from Iran” Annals of Int Med 172(10): 699-701.

Urusov AE, Zherdev AV and Dzantiev BB (2019) “Towards lateral flow quantitative assays: detection approaches”, Biosensors 9: 89.

Vessman J, Stefan RI, Van Staden JF, Danzer K, Lindner W, Burns DT, Fajgelj A and Muller H (2001) “SELECTIVITY IN ANALYTICAL CHEMISTRY (IUPAC Recommendations 2001)” Pure Appl Chem 73(8): 1381-1386.

 Walsh KA et al. (2020) “SARS-CoV-2 detection, viral load and infectivity over the course of an infection” J Infect 81(3): 357-371.

Watkins, J (2020) “Preventing a COVID-19 pandemic” British Medical Journal 368: m810.

WHO (2020a) “Coronavirus disease COVID-19 Weekly Epidemiological Update and Weekly Operational Update”, Situation report(s).

WHO (2020b) “Antigen detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays—Interim Guidance”, Geneva, Switzerland. WHO Ref. No.: WHO/2019-nCoV/Antigen_Detection/2021.1, pp. 1-20.

 Zhou, Y., O’Leary, TJ. Relative sensitivity of anterior nares and nasopharyngeal swabs for initial detection of SARS-CoV-2 in ambulatory patients: Rapid review and meta-analysis. Plos One, July 20, 2021. https://doi.org/10.1371/journal.pone.0254559

[1] including: Abbott (LFA manufacturer), Africa Centres for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Clinton Health Access Initiative (CHAI), Foundation for Innovative New Devices (FIND), the Global Fund, SD Biosensor (LFA manufacturer), Unitaid, and the World Health Organization (WHO)

[2] World Health Organization (WHO), “Global partnership to make available 120 million affordable, quality COVID-19 rapid tests for low- and middle-income countries”, News Release (online), Sept 28, 2020.

Little is known about coronavirus disease 2019 (COVID-19) dynamics and patterns in the African continent (Olyainka et al., 2021).  Evaluation of 224 SARS-CoV-2 genome sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) sequenced early on in the novel COVID-19 (nCoV-2019) outbreak, showed that 69 of the sequences were from Africa.  Mutation classification based on country and region, demonstrates that once a mutation is imported into Africa, subsequent mutations are a certainty.

Investigation of the evolution and genetic diversity of SARS-CoV-2 in Africa reveal, a year ago, a rapidly diversifying SARS-CoV-2 population (Motayo et al., 2020, in one year (Mar 1, 2020 – Jan 7, 2021), led to five (5) different lineages that dominated during distinct periods of the pandemic. Of the five lineages, B.1.1 (n = 518 sequences, 9.91% of the diversity) circulated continuously throughout the sampling year, representing an ongoing clade of active mutation. B.1.1 is prevalent in Europe, is a dominant lineage in Asia, and is most prevalent in North America (USA and Canada) [Olayinka et al., 2021]. This represents widespread high order prevalence across 4 of the largest continents.  Thus, the emergence of B.1.1.529 (Omicron), a branch off B.1.1 that was  first detected in Botswana, November 9, 2021, now a variant of concern because of its partial immune escape mutation profile (European Centre for Disease Prevention and Control, 2021), highlights the importance of reducing the reproductive number, R, i.e. transmissibility of detrimental mutations that may originate and/or circulate through Africa by ensuring resources are on-hand for the treatment of remote villages and communities at a population scale. Because B.1.1.529 (Omicron) shows signs of escaping current vaccines, it represents an inflection point in the virus’ threat profile, bringing Africa sharply into focus in terms of how critical and vital it is to secure Africa, where Omicron can reservoir in asymptomatic hosts, against Omicron and SARS-CoV-2/COVID-19, in general, for Europe, Asia and North America to survive SARS-CoV-2’s evolution.

Africa is the world’s least vaccinated continent and the origin of a number of SARS-CoV-2 variants. Africa is also the continent with the most immunocompromised population and multiple adverse socioeconomic factors and barriers to equitable healthcare access. For example, the current locus of activity of the Omicron variant in Africa is in South Africa, the origin of two variants: the Beta variant and C.1.2. South Africa is a deeply unequal society.[1] Only 16% of South Africa’s population has access to medical aid,[2] with most of its population relying on the public healthcare sector that is under resourced. In addition, the South African healthcare system carries a significant burden of tuberculosis (TB), HIV, and HIV/TB co-infection, with millions of the population on immunosuppressant drugs as well as others who are HIV positive, but not receiving treatment for HIV.[3]  This raises concerns that those with these immunosuppressing co-morbidities are more susceptible to SARS-CoV-2 infections and have a higher risk of developing severe COVID-19 disease.[4]  In this regard, South Africa has the world’s largest HIV epidemic, with an estimated 8.2 million people infected. While most take antiretrovirals, many do not and neighboring countries also have very high HIV infection rates.

Throughout the continent, the burden of diseases is higher than most parts of the world. Diseases like TB are rampant and extreme poverty means that millions are in ill health and have little ability to fight off infections. The longer COVID-19 persists in its host, the longer it sheds, replicates/reproduces, the greater probability it will mutate.  In fact, “there is good evidence that prolonged infection in immunocompromised individuals is one mechanism for the emergence” of COVID-19 variants, such as Omicron, said Tulio de Oliveira, a bioinformatics and genetics professor who heads Next Generation Sequencing (NGS) institutions at 2 South African universities[5], including University of KwaZulu-Natal in Durban.  In fact, it raises the question if “HIV patients whose infections are not controlled with medication could ‘become a factory of variants for the whole world” according to de Oliveira.[6]

24.1 The Cost of One (1) False Positive

Certainly, false-positive COVID-19 test results impose significant costs and hidden problems–categorically, both macro- (globally) and micro- (individually) [Surkova et al., 2020]. As costly as it may be personally to the individual, the cost to society is quantified in Du et al. (2021) as US $3,835.62/2 weeks (14 days) of life lost according to their multiscale model, which describes SARS-CoV-2 transmission both at the population scale (macro) and daily viral load dynamics at the individual scale (micro). This cost assumes daily testing at US $5/test combined with a 2-week self-quarantine period because of the false-positive test result [Du et al., 2021]. US $5 is designated as the price point per unit by a set of agreements between global organizations at the highest levels[1] to make available 120 million LFAs to 2nd and 3rd world countries[2] (note: as far as the USA is concerned, this cost basis underestimates current wholesale prices for antigen-based Rapid Diagnostic Tests (RDTs) in the market by about ½ [Mike Membrino, NAD, personal communication]), which may be why it is frequently chosen as the cost per antigen-based RDT in published models (Atkeson et al., 2020; Ricks et al., 2021 and WHO, 2020b). Comparably, Ricks et al. (2021) models the cost of isolation/day in a hospital setting to be US $50-350/day (an average of $200/day) [Nagarajan R, 2020; Netcare Hospitals, 2019 and Reddy et al., 2020] for a duration of isolation of 10 days (Ricks et al., 2021).  At the upper limit of US $350/day x 10 days, this amounts to US $3,500/10 days of life lost, which compares favorably to the modeled estimate of the multiscale model.

If anything, the cost basis is a lower bounds, since there are many COVID-19 edge cases that cost the employer, including but not limited to: 1. despite vaccination, a subgroup suffer “breakthrough” infections; 2. despite getting infected, a subgroup experience re-infection(s); 3. post-infection, a subgroup, called COVID-19long haulers” continue to suffer, on an ongoing basis, COVID-19-associated sign(s) and symptom(s), requiring leave(s) of absence or “sick days off”, costing the employer lost productivity and opportunity cost(s) and 4. for the rest, the reality that COVID-19, like the flu, will be an ongoing, recurring threat, constantly mutating into new variant(s) that may resist/escape vaccination and/or require new vaccination, treatment, and serial testing.

Across 173 datasets and 124 studies, a total of 61 different antigen-based RDTs (48 LFAs with visual readout) were evaluated (Brummer et al., 2021). Across all meta-analyzed studies (124), when antigen-based RDTs were performed according to manufacturer’s recommendations, they showed a diagnostic sensitivity of 76.3% (95% CI: 73.1% to 79.2%) with SD Biosensor’s STANDARD Q nasal (80.2% diagnostic sensitivity [95% CI 70.3% to 87.4%]) performing best [The PLoS Medicine Staff, 2021]. In stark contrast, a Cochrane review (Dinnes et al., 2021), across 48 studies, evaluating 58 antigen tests, using data from instructions for use (IFU)-compliant tests in symptomatic participants, contradicted Brummer et al. (2021), reporting summary diagnostic sensitivities ranging from 34.1% (95% CI: 29.7% to 38.8%) to 88.1% (95% CI: 84.2% to 91.1%), but with SD Biosensor STANDARD Q also performing best (Dinnes et al., 2021). Of note, average specificities were high in symptomatic and asymptomatic participants, and for most brands demonstrated an overall summary diagnostic specificity of 99.6% (95% CI:99.0% to 99.8%).

At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), the global standards for LFAs for the 2nd and 3rd world countries (120 million units projected to be distributed), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results (average: 1 in 8 [16.67%]) will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed (false negative).

Contrast this with NAD’s AN offering with a diagnostic sensitivity of 95.6% and a diagnostic specificity of 100% (see Results, preceding).  By eliminating false positives, companies will save an estimated US $3,500 – $3,835.62/employee saved from isolation. Considering NAD’s low COGS for its LFA, a 1% investment by an employer (US $3.50 – $3.83/test kit) can return a 100x return in potential cost savings without the liability and risk exposure of 99% of the LFA test kits on the market.

Moreover, its temperature stability (2-month stability at a sustained 100 with a combined 15-month shelf life at room temperature) [IHL/SD, personal communication] and robust response to POC stress (300% excess drops of reagent by operator error) make it the most accurate and durable LFA in the market today. Effective therapy is only possible when a disease is diagnosed quickly and reliably (Urusov et al., 2019). The key characteristics of an ideal IVD are that it is both accurate, durable, and low cost.  In the case of the NAD Lateral Flow Nucleo-Option(™) COVID-19 Rapid Antigen Test, there is no need to tradeoff any of the 3 features.

24.2 Global Population Public Health Protocol at Scale

Current real-time estimates of the effective Reproduction Rate (Re) [Achaiah et al., 2020] for COVID-19 worldwide curve-fit at: 1.06 (Nov 17, 2021; 7:57 am EST, model dashboard) using a Kalman filter (Arroyo-Marioli et al., 2021)–indicating slow (and low) transmission worldwide, on average.

Figure 5, Real-Time Estimates of the global Re

Such forecasting is critical (Achaiah et al., 2020) because Du’s multiscale modeling (Du et al., 2021) shows a cost-effective testing strategy under low transmission (Re of 1-2) scenarios of monthly testing of a population followed by 1 week isolation rather than the current 2 weeks (Du et al., 2021) and that expanded surveillance testing is more likely to be cost-effective than the current status-quo testing if the price per test is less than US $75 across any and all transmission rates modeled. Further modeling favors serial testing with LFAs only and Bayesian statistical analysis to obviate the need for a time-consuming confirmation by PCR (Ferretti et al., 2021). Frequent LFA with an economical, accurate and durable antigen-based RDT, such as the NAD Lateral Flow Nucleo-Option™ COVID-19 Rapid Antigen Test is needed now for COVID-19 population health testing at scale as we approach COVID-19 global endgame scenarios (Kofman et al., 2021).

In conjunction with serial screening, we have to be extremely discriminatory in the selection process of RDTs and the process of RT-PCR has to be converted away from its use as a screening tool and more as an active false positive diagnostic alert tool, if anything, at the very least, after a 2nd RDT to backstop discrepancies between RDTs and for QA/QC as we shift towards mandated testing (reflected by the Biden Mandate) and pervasive testing and contact tracing. It is now the LFIA/LFA doing agile discovery for us on our front lines and in the trenches.

25       References

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