key: cord-0949244-9m2cgcm9
authors: Mlcochova, Petra; Collier, Dami; Ritchie, Allyson; Assennato, Sonny M.; Hosmillo, Myra; Goel, Neha; Meng, Bo; Chatterjee, Krishna; Mendoza, Vivien; Temperton, Nigel; Kiss, Leo; James, Leo C.; Ciazynska, Katarzyna A.; Xiong, Xiaoli; Briggs, John AG.; Nathan, James A.; Mescia, Federica; Bergamaschi, Laura; Zhang, Hongyi; Barmpounakis, Petros; Demeris, Nikos; Skells, Richard; Lyons, Paul A.; Bradley, John; Baker, Steven; Allain, Jean Pierre; Smith, Kenneth GC.; Bousfield, Rachel; Wilson, Michael; Sparkes, Dominic; Amoroso, Glenn; Gkrania-Klotsas, Effrosyni; Hardwick, Susie; Boyle, Adrian; Goodfellow, Ian; Gupta, Ravindra K.; Baker, Stephen; Dougan, Gordon; Gupta, Ravi; Lehner, Paul J.; Lyons, Paul; Matheson, Nicholas J.; Smith, Kenneth G.C.; Toshner, Mark; Weekes, Michael P.; Brown, Nick; Curran, Martin; Palmar, Surendra; Enoch, David; Chapman, Daniel; Shaw, Ashley; Jose, Sherly; Bermperi, Areti; Zerrudo, Julie Ann; Kourampa, Evgenia; Watson, Laura; Worsley, Jieniean; Saunders, Caroline; de Jesus, Ranalie; Domingo, Jason; Pasquale, Ciro; Vergese, Bensi; Vargas, Phoebe; Fabiculana, Marivic; Perales, Marlyn; Mynott, Lee; Blake, Elizabeth; Bates, Amy; Vallier, Anne-Laure; Williams, Alexandra; Phillips, David; Chiu, Edmund; Overhill, Alex; Ramenatte, Nicola; Sipple, Jamal; Frost, Steven; Knock, Helena; Hardy, Richard; Foster, Emily; Davidson, Fiona; Rundell, Viona; Bundi, Purity; Abeseabe, Richmond; Clark, Sarah; Vicente, Isabel; Elmer, Anne; Ribeiro, Carla; Kourampa, Jenny; Kennet, Jane; Rowlands, Jane; Meadows, Anne; O’Brien, Criona; Rastall, Rebecca; Crucusio, Cherry; Hewitt, Sarah; Price, Jane; Calder, Jo; Canna, Laura; Bucke, Ashlea; Tordesillas, Hugo; Harris, Julie; Ruffolo, Valentina; Graves, Barbara; Butcher, Helen; Caputo, Daniela; Le Gresley, Emma; Dunmore, Benjamin J.; Martin, Jennifer; Legchenko, Ekaterina; Treacy, Carmen; Huang, Christopher; Wood, Jennifer; Sutcliffe, Rachel; Hodgson, Josh; Shih, Joy; Graf, Stefan; Tong, Zhen; Tilly, Tobias; O’Donnell, Ciara; Hunter, Kelvin; Pointon, Linda; Pond, Nicole; Wylot, Marta; Jones, Emma; Fawke, Stuart; Bullman, Ben; Turner, Lori; Jarvis, Isobel; Omarjee, Ommar; De Sa, Aloka; Marsden, Joe; Betancourt, Ariana; Perera, Marianne; Epping, Maddie; Richoz, Nathan; Bower, Georgie; Sharma, Rahul; Nice, Francesca; Huhn, Oisin; Yarkoni, Natalia Savoinykh; Romashova, Nika; Lewis, Daniel; Hinch, Andrew; Cossetti, Chiara; Strezlecki, Mateusz; Grenfell, Richard; Stark, Hannah; Walker, Neil; Stirrups, Kathy; Ovington, Nigel; Dewhust, Eleanor; Li, Emily; Papadia, Sofia
title: Combined point of care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G Spike Variant
date: 2020-09-01
journal: Cell Rep Med
DOI: 10.1016/j.xcrm.2020.100099
sha: 6c6cd899e26593339586a7bdb4ec3a45d18dac1d
doc_id: 949244
cord_uid: 9m2cgcm9

Rapid COVID-19 diagnosis in hospital is essential, though complicated by 30-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant now dominates the pandemic and it is unclear how serological tests designed to detect anti-Spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95CI 57.8-92.9%) by rapid NAAT alone. Combined point of care antibody test and rapid NAAT is not impacted by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

As of the 2 nd of August 2020, more than 18.0 million people have been infected with SARS-CoV-2 with over 690,000 deaths 1 . The unprecedented numbers requiring SARS-CoV-2 testing has strained healthcare systems globally. There is currently no gold standard for diagnosis of COVID-19. Detection of SARS-CoV-2 by nucleic acid amplification testing (NAAT) is largely done by real time RT-PCR on nose/throat swabs in centralised laboratories. RT-PCR specimens are often batch analysed and the turnaround time for this test can be as long as 2-4 days in real world settings 2 . NAAT tests from a single nose/throat swab are negative in up to 50% in patients who have CT changes consistent with and/or positive antibodies to SARS-CoV-2 [3] [4] [5] . The lack of detectable virus in upper airway samples is not only a serious barrier to making timely and safe decisions in the emergency department, but also leads to multiple swab samples being sent, frequently from the same anatomical site, leading to additional strain on virology laboratories. Nonetheless, NAAT remains important in identifying infectious individuals. Additionally, in severely ill patients J o u r n a l P r e -p r o o f tracheo-bronchial samples might be NAAT positive even when the nose/throat swab is negative 4, 6 .

Multiple factors might contribute to negative results by NAAT, including test sensitivity, sampling technique and timing of the sampling in the disease course 6 . The viral load in the upper respiratory tract is detectable from around 4 days before symptoms 7 and frequently wanes after a week post symptom onset 8 9 . Similarly, a case series from Germany found the detection rate by RT-PCR was <50% after 5 days since onset of illness 10 . A proportion of patients develop a secondary deterioration in clinical condition requiring hospitalisation and respiratory support, at a time when immune pathology is thought to be dominant rather than direct pathology related to viral replication 9, 11 .

An antibody response to SARS-CoV-2 is detectable 6 days from infection and is almost always neutralising 12, 13 . Antibody based diagnosis of COVID-19 shows increasing sensitivity in the latter part of the infection course when NAAT testing on nose/throat samples is more likely to be negative [14] [15] [16] [17] . As a result, diagnosis of infection as well as identification of infectivity would benefit from a combination of virologic and immunologic markers to inform patient initial triage and subsequent management. It is critical to determine whether a rapid point of care combined antibody and nucleic acid testing strategy could improve diagnosis.

We previously evaluated the diagnostic accuracy of the SAMBA II SARS-CoV-2 rapid test compared with the standard laboratory RT-PCR and found similar accuracy with a turnaround time of 2-3 hours even in real world settings 18 . Several studies have now reported head-to-head comparisons of immuno-chromatographic lateral flow immunoassays (LFAs) [15] [16] [17] 19 . These assays are cheap to manufacture and give a binary positive/negative result, thereby lending themselves well to point of care (POC) testing. Even though they have variable performance and in general are negative in the early phase of infection, they become highly sensitive in the later stage of illness [15] [16] [17] 19 and some are also highly specific.

In this study we evaluated the diagnostic performance of a POC combination comprising NAAT and antibody testing against a composite reference standard of laboratory RT-PCR and a serum neutralisation assay. Notably, SARS-CoV-2 viruses with a D to G mutation in Spike at position 614 have increased in prevalence globally 20 . Cryo EM studies suggest that J o u r n a l P r e -p r o o f D614 may play a role in Spike inter-molecular stability 21 , potentially contributing to increased infectivity 20 . Given POC antibody tests were designed to detect antibodies to wild type S protein, we also aimed to investigate whether SARS-CoV-2 infections with D614G Spike mutant virus could be diagnosed by POC antibody tests.

In phase one, 45 prospectively recruited participants in the COVIDx study with suspected COVID-19 disease had nose/throat swabs specimens tested for nucleic acid as well as stored sera for antibody testing. Samples at hospital admission were collected at a median of 7 (IQR 7-13) days after illness onset. The sera from 42.2% (19/45) participants showed neutralising antibody response against SARS-CoV-2 Spike protein pseudotyped virus infection in a neutralisation assay using a cut-off of 50% inhibition at 1:4 dilution ( Figure 1A ). 26

participants' sera showed no neutralising response ( Figure 1B ). The neutralisation ability of participants' sera was compared with an in house ELISA IgG assay for Spike specific antibodies based on a recently reported method 22 J o u r n a l P r e -p r o o f However, 6/24 (25%) had normal or indeterminate chest radiographs in the confirmed COVID-19 group.

As expected from the clinical study inclusion criteria, more than 80% of patients presented with influenza like illness (ILI) with documented fever and approximately one third had clinical or radiological evidence of pneumonia (Table 1) . Highly experienced internal medicine physicians were caring for suspected COVID-19 cases at our institution, and this was partly due to the significant co-morbidities in the local population that mandated a broad differential diagnostic approach in hospitalised individuals (Table 1) . Amongst patients with COVID-19 one suffered from rheumatoid arthritis and was currently immunosuppressed with Prednisolone. Amongst patients without COVID-19, five were immunosuppressed for the following conditions: psoriatic arthritis -Usekinumab (anti IL-12, IL-23); multiple myeloma -Lenalidomide and dexamethasone; Lymphoma -ciclosporin; hypersensitivity pneumonitismycofenalate and prednisolone; renal transplant -mycofenalate and tacrolimus. No patients in the study were under treatment with the anti-B cell monoclonal antibody rituximab.

During the peak of the first wave routine respiratory virus testing was halted at our institution due to the demands of SARS-CoV-2 testing and low seasonal prevalence of these pathogens.

Multiplex PCR for other respiratory viral pathogens was performed in only 8 participants.

Seven of these participants were negative and one participant tested positive for influenza A.

The overall COVID-19 diagnosis rate (positive predictive agreement) by rapid nucleic acid testing was 79.2% (95% CI 57.8-92.9), decreasing from 100% (95% CI 65.3-98.6%) for days 1-4 to 50.0% (95% CI 11.8-88.2) for days 9-28 post symptom onset (Table 2 Figure 3A , B). 14/24 (58.3%) patients deemed to be COVID-19 positive by the reference composite standard were positive by both rapid NAAT and antibody testing and 14/14 were infected with strains bearing D614G, indicating that point of care serological tests were able to detect infections with this variant.

To understand the relationship between POC band intensity and neutralisation activity further, we identified three participants (all infected with D614G Spike mutant) with stored samples at multiple time points in their illness ( Figure 4 ). Two individuals were sampled from early after symptom onset and the third presented three weeks into illness. In the first two cases ( Figure 4A -F), we observed an increase in neutralisation activity over time that was mirrored by band intensities on rapid POC antibody testing. As expected IgM bands arose early on with IgG following closely. Of note in patient 1 there was a weakly detectable IgM band by rapid test with no serum neutralisation activity ( Figure 4A , B). Over time the band intensity for IgM and IgG increased along with serum neutralisation activity. In the individual presenting 21 days into illness ( Figure 4G -I), only IgG was detected with rapid POC antibody testing and as expected band intensity did not increase over the following days.

In phase 2, we performed a prospective evaluation of combined testing in 128 patients presenting with possible COVID-19 from July 13 th to 27 th 2020. Their clinical presentation was less severe and diagnoses broader than in phase 1 (Table 3) , with cardiovascular and gastrointestinal disease significantly represented and respiratory disease representing just 60% of cases -likely as a result of the increased appreciation of diverse presentations of COVID-19 disease 23 . Patients did have significant comorbidities and around 10% were immune suppressed, though without B cell depleting agents (Table 3 ). By this time the POC NAAT test had been validated in a head to head study against the lab RT-PCR and entered routine use (Collier et al., 2020) , replacing the RT-PCR. Given the need to further assess the specificity of the POC antibody tests in routine clinical practice and with fresh blood rather than serum, we compared the performance of POC antibody tests on finger prick blood against serum neutralisation ( Figure 5A and B).

In this second phase there was only one NAAT positive case, who was also positive by both POC antibody tests and serum neutralisation. There were three NAAT negative individuals presenting with respiratory symptoms who had positive POC antibody tests by both J o u r n a l P r e -p r o o f COVIDIX and SureScreen, along with serum neutralisation activity. The POC antibody tests showed 100% negative predictive agreement with serum neutralisation and the kappa correlation between POC antibody tests and serum neutralisation was extremely high at 0.97.

Here we have shown that POC NAAT testing in combination with antibody detection can significantly improve diagnosis of COVID-19. Overall positive predictive agreement against the composite reference standard under clinical trial conditions was around 79% for rapid NAAT testing of nose/throat swab samples, reaching 100% with a combined approach of rapid NAAT testing and either of the two POC lateral flow-based antibody tests. The specificity of the combined approach was 85-95% on stored serum under clinical trial conditions and 100% on fingerprick blood in routine clinical care.

As expected, nucleic acid detection in nose/throat samples was highest in those presenting within the first few days (100% in samples taken in the first 4 days after symptom onset).

Conversely antibody detection by LFA increased with time since symptom onset with 100% efficacy beyond 9 th day post-symptoms. One study reported that combined lab based RT-PCR with lab based antibody testing could increase sensitivity for COVID-19 diagnosis from 67.1% to 99.4% in hospitalised patients 24 . However, in that study this assessment of sensitivity was made using clinical diagnosis. A major strength of this study is the use of an objective reference standard that included NAAT and serum neutralisation -a phenotypic test for functionality of antibodies. This assay was shown to be robust and accurate, using a recently described ELISA method for SARS-CoV-2 IgG detection that is now used

The D614G Spike mutant has spread globally. Wild type Spike protein antigen is used in the development and validation of POC antibody tests, including those tested here. Of critical importance is the fact that both POC antibody tests (and ELISA) were able to detect antibody responses in patients infected with the D614G Spike mutant and that band intensity of POC testing increased with neutralisation activity in these individuals. Given that POC antibody tests are far cheaper and simpler to deploy, they will likely be used in low resource settings that do not have access to NAAT 25 . Demonstration that POC antibody LFA tests can detect the D614G spike mutant is therefore of importance.

Use of antibody tests for COVID-19 diagnosis in hospitals has been limited for a number of reasons. Firstly, we know from SARS-CoV-1 that previous humoral immunity to HCoV OC43 and 229E can elicit a cross-reactive antibody response to N of SARS-CoV-1 in up to 14% of people tested in cross-sectional studies 26 , and previous exposure to HCoV can rarely elicit a cross-reactive antibody response to the N and S proteins of SARS-CoV-2 16, 27 .

Secondly, antibody tests do not achieve the same detection rates as nucleic acid based tests early in infection, as humoral responses take time to develop following viral antigenic stimulation. However, by day 6 post symptom onset detection of IgG to Spike protein has been reported to reach 100% sensitivity 12 and this is useful in cases with immune mediated inflammatory disease where RT-PCR on respiratory samples is often negative, for example in the recently described Kawasaki-like syndrome named PIMS (paediatric inflammatory multisystem syndrome) 28 .

In phase one (COVIDx trial) we tested stored sera rather than whole blood finger prick, though this was intentional given the caution needed in interpreting LFAs and concern regarding potential cross-reactivity of antibodies and poor specificity. Although SARS-CoV-2 ELISA testing of our pre-pandemic sera did reveal occasional N reactivity to SARS-CoV-2, likely due to cross reactivity with seasonal CoV, these samples were negative on POC antibody testing. However, the specificity of the COVIDIX test was estimated at only 85%, compared to a more acceptable 95% for SureScreen. We therefore carried out prospective evaluation of POC antibody testing on finger prick blood in 128 suspected cases of COVID-19 in order to further evaluate specificity of both tests in routine clinical practice. We found no false positives in patients whose sera were non-neutralising. This is consistent with an estimated specificity of above 99% with the SureScreen assay observed in an independent analysis using stored pre-pandemic sera 29 . The greater incidence of false positive POC antibody tests, predominantly with COVIDIX, on stored sera as compared to fresh finger prick blood may be due to processing and storage of sera, contamination of sera with other blood products, or other causes, including patient factors that differed between the two phases. Nevertheless, now that we are in a low incidence period it is advisable to perform confirmation testing using an alternative platform for either a single positive antibody or NAAT test, as is now the policy at our institution. One should note in particular that antibody tests may be negative in patients with immune suppression, highlighting that patient factors can influence interpretation of results and that alternative diagnoses should be considered.

We envisage a deployment approach whereby both test samples, finger prick whole blood and nose/throat swab, are taken at the same time on admission to hospital. The finger prick antibody test result is available within 15 minutes. Due to the possibility of false positive results from POC serology testing, a positive POC antibody test result as the only positive marker should ideally be confirmed with a second rapid POC test / laboratory IgG/IgM test before movement to a COVID-19 area, or recruitment into a clinical treatment study. At our institution further diagnostic data from chest imaging and blood indices such as lymphocyte count and C-reactive protein when assessing patients for COVID-19 and clinical decision making. Further swabs for NAAT testing are also taken where possible.

A confirmed positive NAAT result remains critical not only to identify early infection but, more importantly to triage infectious patients to be isolated from other patients and be handled with particular care by staff. NAAT is also valuable in milder and asymptomatic cases given severity appears to correlate with magnitude of antibody responses 16, 30 . In conclusion rapid combined testing could be important in diagnosis and management of COVID-19, particularly given the pandemic is not well controlled in many parts of the world and as diverse manifestations of disease emerge.

This study was limited by the fact that it was conducted at a single centre with relatively small numbers of individuals in the clinical study (phase 1), largely due to a lack of available stored serum. Phase 1 of the study used stored serum where there was a higher false positive rate than phase 2 where whole blood was used. The implementation study (phase 2) had greater numbers and was able to effectively demonstrate the high specificity of POC antibody tests and very low false positive rate for both POC antibody tests on whole blood, though itself was hampered by the low incidence of COVID-19 infection during the period it was undertaken. This low incidence rate in phase 2 limited further evaluation of the sensitivity of the combined approach. There was also a lack of data on repeated sampling and sampling from deeper respiratory sites in those suspected cases who were NAAT negative. Future larger studies are warranted. 

The authors declare no competing interests . 

Further information should be directed to and will be fulfilled by the Lead Contact, Ravindra K. Gupta rkg20@cam.ac.uk.

This study did not generate new unique reagents.

Raw anonymised data are available from the lead contact without restriction.

The study was conducted in two phases; a clinical validation phase followed by an implementation phase. The study participants in phase one were part of the COVIDx trial 18 

The standard laboratory RT-PCR test, developed by public health England (PHE), targeting the RdRp gene was performed on a combined nose/throat swab. This test has an estimated limit of detection of 320 copies/ml. In parallel, SAMBA II SARS-CoV-2 testing was performed on a combined nose/throat swab and inactivated in a proprietary buffer at the point of sampling. SAMBA II SARS-CoV-2 targets 2 genes-Orf1 and the N genes and uses nucleic acid sequence based amplification to detect SARS-CoV-2 RNA, with limit of detection of 250 copies/ml. 31 Steady-Glo Luciferase assay system (Promega). incubation in a 5% CO 2 environment at 37°C, the luminescence was measured using Steady-Glo Luciferase assay system (Promega).

We developed an ELISA targeting the SARS-CoV-2 Spike and N proteins. Trimeric spike protein antigen used in the ELISA assays consists of the complete S protein ectodomain with a C-terminal extension containing a TEV protease cleavage site, a T4 trimerization foldon and a hexa-histidine tag. The S1/S2 cleavage site with amino acid sequence PRRAR was replaced with a single Arginine residue and stabilizing Proline mutants were inserted at positions 986 and 987. Spike protein was expressed and purified from Expi293 cells (Thermo Fisher). N protein consisting of residues 45-365 was initially expressed as a His-TEV-SUMO-fusion. After Ni-NTA purification, the tag was removed by TEV proteolysis and the cleaved tagless protein further purified on Heparin and gel filtration columns.

The ELISAs were in a stepwise process; a positivity screen was followed by endpoint titre as previously described 22 Blocking solution was aspirated and the diluted sera were added to the plates and incubated for 2 hours at ambient temperature. Diluted sera were removed, and plates were washed three times with PBST. Goat anti-human IgG secondary antibody-Peroxidase (Fc-specific, Sigma) prepared at 1:3,000 in PBST was added and plates were incubated for 1 hour at ambient temperature. Plates were washed three times with PBST. ELISAs were developed using 3,5,3′,5′-tetramethylbenzidine (TMB, ThermoScientific); reactions were stopped after 10 minutes using 0.16M Sulfuric acid.

This colloidal-gold lateral flow immunoassay is designed to detect IgG and IgM to SARS- 

• Combined rapid antibody + nucleic acid detection correctly diagnoses SARS-CoV-2

• Rapid antibody tests detect immune responses against SARS-CoV-2 bearing D614G

• Rapid SARS-CoV-2 antibody tests do not cross react with antibodies to seasonal CoV

• False positivity in SARS-CoV-2 finger prick blood antibody tests can be very low.

Mlcochova et al. report that combined rapid nucleic acid amplification testing (NAAT) and finger prick blood antibody tests can substantially improve diagnosis of COVID-19 as compared to NAAT alone and are able to detect the SARS-CoV-2 Spike D614G variant that dominates the pandemic.

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