Sep 9, 2021

BioVaxys' COVID T Cell Diagnostic Shows Positive Human Data. Shares Surge!

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Based in Vancouver, BioVaxys Technology Corp. is a British Columbia-registered, clinical-stage biotechnology company that is developing viral and oncology vaccine platforms, as well as immuno-diagnostics. The Company is advancing a SARS-CoV-2 vaccine based on its haptenized viral protein technology and is leveraging this platform to develop a diagnostic ("CoviDTH")for evaluating the presence or absence of a T cell immune response to SARS-CoV-2, the virus that causes COVID-19.

On July 22, 2021, the company received positive feedback from the FDA stating that their clinical development program for their CoviDTH diagnostic is strong enough to submit an IND for a combined Phase I/II human clinical trial (IND is currently being prepared). Recent human data strongly indicates that the CoviDTH diagnostic is capable of detecting durable, cellular immunity in patients that have either received the vaccine or been previously infected. The CoviDTH test relies on the concept of Delayed-Type Hypersensitivity (DTH), which is known to be a measure of T cell activity and has been used for many years for other infectious diseases (tuberculosis, fungal diseases, mumps). Similar to an allergy skin test, CoviDTH works by placing a small amount of synthesized test material (recombinant SARS-Cov-2 s-protein) intradermally and inspecting the site for erythema and induration 24-48 hours later (skin appears slightly red and swollen). CoviDTH is a patent-pending, disposable syringe with a micro needle that delivers a small amount of fully-characterized, purified, non-infectious, synthesized SARS-CoV-2 s-1 protein in liquid suspension.

BioVaxys is also preparing for a clinical trial (European Union, early 2022) of its haptenized autologous cell vaccine used in combination with anti-PD1 and anti-PDL-1 checkpoint inhibitors that will initially be developed for ovarian cancer. BioVaxys common shares are listed on the CSE (CSE: BIOV) and trades on the Frankfurt Bourse (FRA: 5LB) and in the US (OTCQB: BVAXF).

Background

T cells and immunity

The COVID-19 pandemic may as well be called the COVID-21 plague, as hospitalizations and death toll continue to skyrocket due to the emergence of new SARS-CoV-2 variants around the world. Our body’s immune systems are adaptive, capable of creating an army of pathogen-fighting scouts and foot-soldiers to locate and eradicate the viral insurgents. To continue the military analogy, viruses engage in guerilla warfare and adapt quickly to the counter-insurgency’s weapons and tactics (the immune system) by way of natural mutation. The Catch-22 of a strong immune response is that the weak virions are eliminated while the better-equipped continue to infect human host cells and replicate exponentially. The insanely fast rate of viral mutation is responsible for creating these better-equipped “super soldiers”. To put this in perspective, the estimate of mutation for HIV-1 predicts that any single mutation conferring drug resistance should occur within a single day of infection [1]. Mutation rates are expressed in units of substitutions per nucleotide per cell infection, which translates to the rate that the DNA (randomly) mutates per the number of infected cells. Both HIV-1 and influenza have similar mutation rates (~2.4 x 10^-5). Luckily, SARS-CoV-2 mutates almost 10x slower (~10^-6) than these two viruses due to its molecular “proofreading” mechanism [2]. This slower mutation rate implies that vaccines developed against the original SARS-CoV-2 virus could have long-lasting effects compared to the flu, which quickly becomes obsolete due to quick influenza strain mutation.

Read MedicalGold's primer on viral infection and the immune system

To investigate the possibility that SARS-CoV-2 variants might escape the adaptive immune system response, created by either prior infection or vaccination, researchers at the National Institute of Allergy and Infectious Diseases (NIAID, part of the National Institutes of Health), analyzed the immune cells found in the blood of 30 patients that were infected but then recovered from COVID-19. The purpose of this study was to identify immune cells (if any) that remain active against SARS-CoV-2 variants. The research team, led by NIAID’S Andrew Redd, PhD, concluded that the cytotoxic T cells (CD8+ T cells) found in previously-infected patient’s blood remain active against three SARS-CoV-2 variants (B.1.1.7, B.1.351, and B.1.1.248). Previous research has shown that the neutralizing antibodies (Nab) response to different variants are variable, so measuring antibody levels in previously-infected patient’s blood is unlikely to indicate whether that patient will be immune to other variants. Immunity against SARS-CoV-2 variants is most likely conferred by T cell activity [3]; identifying the presence of these T cells targeted against SARS-CoV-2 will inform clinicians and patients about their likelihood of contracting newly mutated strains.

BioVaxy’s CoviDTH Diagnostic

The T cell advantage

Current COVID-19 tests only measure antibodies (“humoral immunity”), ignoring the powerful, broad-spectrum T cell effect (“cellular immunity”). Recent findings suggest that antibody levels decline significantly within 90 days of infection or vaccination, but T cell activity is both durable and robust against viral variants (see “The data is in” section below). Current tests for cellular immunity require 2-ounce blood draws and are time consuming and expensive to run. There is a clear unmet need for a cellular immunity test that can be cheaply manufactured, broadly distributed, and can detect immunity against SARS-CoV-2 variants as they emerge.

BioVaxy’s CoviDTH is a cost efficient and fast turn-around diagnostic, and unlike other diagnostics does not require a blood sample. CoviDTH is based on the principle of Delayed-Type Hypersensitivity (DTH), which is known to be a measure of T cell activity and has been used for many years for other infectious diseases (tuberculosis, fungal diseases, mumps). Similar to an allergy skin test, CoviDTH works by placing a small amount of synthesized test material (recombinant SARS-Cov-2 s-protein) intradermally and inspecting the site for erythema and induration 24-48 hours later (skin appears slightly red and swollen). CoviDTH is a patent-pending, disposable syringe with a micro needle that delivers a small amount of fully-characterized, purified, non-infectious, synthesized SARS-CoV-2 s-1 protein in liquid suspension. The test results can be measured with a ruler or a cell phone app that BioVaxys is developing. The diagnostic is a platform technology, meaning that it can be applied to detect multiple SARS-CoV-2 variants by synthesizing and applying the unique spike proteins from each variant. CoviDTH has the potential to detect T-cell responses related to emerging variants such as the B.1.1.7 and 501Y.V2, as well as others such as the delta and lambda variants.

The CoviDTH diagnostic is superior to antibody tests because…

  • Antibody levels decline over time, while T cell responses are long-lasting.
  • T cells may recognize different patterns of antigens (viral proteins) than antibodies recognize.
  • The precise antigens used in antibody tests are poorly characterized, so it is not possible to know whether those antibodies being measured have a neutralizing effect on the virus.
  • The FDA has issued a warning against using antibody tests be used to assess immunity, implying that the antibodies being measured may or may not kill the virus.

BioVaxys received word from the FDA that the company’s clinical plan is adequate to file an Investigational new Drug (IND) application to enter a combined Phase I/II safety and dosing/efficacy study without needing to perform an animal toxicity study. The Agency also concluded that the Chemistry, Manufacturing and Controls section of their application is acceptable, meaning that the manufacturing process is well-defined and ready to be produced at scale (Learn more about BioVaxy’s manufacturing agreement for SARS-CoV-2 vaccine and diagnostic program).

The data is in, and it looks good

Yvelise Barrios, MD, PhD (Bioavxys’ Scientific Advisor on the CoviDTH program recently presented the results of a long-term follow-up of the T cell response in patients who successfully recovered from SARS-CoV-2 at the 6th European Congress of Immunology. This small+ study examined two recovered patients at 6- and 12-months post-infection. The DTH responses (Subject A: 6 months=41mm, 12 months=35mm; Subject B: 6 months=14mm, 12 months=30mm) are considered very large compared to DTH tests for other infections (such as tuberculosis). This is the first long-term follow-up that validates Biovaxys’ two previous studies on T cell immunity acquired from vaccination or natural exposure to SARS-CoV-2, and clearly demonstrates that DTH is a simple and effective way to measure a durable immune response (as opposed to the transient antibody response that diminishes over time). An independent research group confirmed that T cells are active at 6 months following infection [4] Taken together, the data strongly suggests that T cells are both reactive and can be detected months to years after infection.

Dr. Barrios and her team previously conducted two independent investigations into the DTH cellular response to patients exposed to SARS-CoV-2 (May 2021) and to vaccination with the Pfizer mRNA vaccine (July 2021). In their first study, the researchers confirmed that DTH using the SARS-CoV-2 spike (s-) protein was both highly specific (no positive results were recorded for individuals who were not exposed to the virus) and highly sensitive (43 of the 51 individuals previously exposed to the virus yielded positive DTH results). A comparison of the standard antibody-based immunity test and the DTH test produced 84.3% concordance, with the DTH test producing more stable results over time and detecting 7 positive scores that the antibody test determined to be negative [5]. The second study of DTH response in vaccinated (Pfizer) individuals showed even better results, with 28 out of 28 vaccinated participants producing positive scores 14 days after receiving the 2nd dose of the vaccine (on day 36) [6]. Compared to the antibody response to vaccination, DTH takes a couple of weeks longer and requires 2 doses of the vaccine to display cellular immunity, which is in line with the in vitro data that supports memory B cell activity against the spike receptor binding domain (RBD) primed by vaccination and detectable after the 2nd dose [7].

Over 40% and 63% of the global population and Americans have received at least one dose, respectively (Google COVID tracker as of 9/7/2021). These figures are quickly increasing and will accelerate as vaccine production ramps up, full approval is granted to the Moderna and J&J vaccines, and booster shots become more prevalent. Unfortunately, vaccination will not put a complete halt to the pandemic due to the rapid emergence of new variants (delta variant is supposedly twice as infectious as the original virus and makes up 99% of current infections, according to the CDC) and the waning efficacy of vaccines over time (60-78% efficacy after 90 days post 2nd dose) [8]. New data has emerged that suggests that previous infection with a prior variant confers more durable immunity than vaccination alone, likely because the vaccines produce a strong neutralizing antibody response [9] that is specific for the variant while infection with the live virus also activates the broader T and B cellular immune pathways [10]. Moving forward, it will be critical to measure the global population’s cellular immunity to gauge the trajectory of the pandemic.

Biovaxys’ T cell diagnostic program is ahead of the curve.

CoviDTH diagnostic is ready to fill the gaping unmet need.

The Market’s Response

Technical breakout

References

[1] Sanjuán Rafael, Nebot, M. R., Chirico, N., Mansky, L. M., & Belshaw, R. (2010). Viral Mutation Rates. Journal of Virology, 84(19), 9733–9748. https://doi.org/10.1128/jvi.00694-10 [Link}

[2] Manzanares-Meza, L. D., & Medina-Contreras, O. (2020). SARS-CoV-2 and influenza: a comparative overview and treatment implications. SARS-CoV-2 e influenza: revisión comparativa e implicaciones del tratamiento. Boletin medico del Hospital Infantil de Mexico, 77(5), 262–273. https://doi.org/10.24875/BMHIM.20000183. [Link]

[3] AD Redd et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infectious Diseases DOI: 10.1093/ofid/ofab143 (2021). [Link]

[4] Zuo, J., Dowell, A. C., Pearce, H., Verma, K., Long, H. M., Begum, J., Aiano, F., Amin-Chowdhury, Z., Hoschler, K., Brooks, T., Taylor, S., Hewson, J., Hallis, B., Stapley, L., Borrow, R., Linley, E., Ahmad, S., Parker, B., Horsley, A., Amirthalingam, G., … Moss, P. (2021). Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection. Nature immunology, 22(5), 620–626. https://doi.org/10.1038/s41590-021-00902-8 [Link]

[5] Barrios, Y., Franco, A., Sanchez-Machin, I., Poza-Guedes, P., Gonzalez-Perez, R., & Matheu, V. (2021). A novel application of delayed-type hipersensitivity reaction to measure cellular immune response in SARS-CoV-2 exposed individuals. Clinical immunology (Orlando, Fla.), 226, 108730. https://doi.org/10.1016/j.clim.2021.108730 [Link]

[6] Barrios, Y., Franco, A., Sánchez-Machín, I., Poza-Guedes, P., González-Pérez, R., & Matheu, V. (2021). The Beauty of Simplicity: Delayed-Type Hypersensitivity Reaction to Measure Cellular Immune Responses in RNA-SARS-Cov-2 Vaccinated Individuals. Vaccines, 9(6), 575. https://doi.org/10.3390/vaccines9060575 [Link]

[7] Doria-Rose, N., Suthar, M. S., Makowski, M., O’Connell, S., McDermott, A. B., Flach, B., Ledgerwood, J. E., Mascola, J. R., Graham, B. S., Lin, B. C., O’Dell, S., Schmidt, S. D., Widge, A. T., Edara, V.-V., Anderson, E. J., Lai, L., Floyd, K., Rouphael, N. G., Zarnitsyna, V., … Kunwar, P. (2021). Antibody persistence through 6 months after the second dose OF mrna-1273 vaccine FOR COVID-19. New England Journal of Medicine, 384(23), 2259–2261. https://doi.org/10.1056/nejmc2103916 [Link]

[8] COVID vaccines protect against Delta, but their effectiveness wanes [Link]

[9] Planas, D., Veyer, D., Baidaliuk, A. et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 596, 276–280 (2021). https://doi.org/10.1038/s41586-021-03777-9 [Link]

[10] Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections [Link]

Disclosure

Author owns BIOV.CA shares at the time of publishing and may choose to buy or sell at any time without notice. Author has been compensated for marketing services by BioVaxys Technology Corp.

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