At Tonix, History Underpins a Modern Approach to COVID-19 Vaccines

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Tonix Pharmaceuticals TNXP, which has a broad portfolio of COVID-19 vaccines and drugs in development, recently announced it was adapting its core vaccine technology to specifically address the Omicron and BA.2 variants of the SARS-CoV-2 virus.

We recently caught up with Tonix’s CEO, Dr. Seth Lederman, and got in some questions about his views of the Nation’s needs and path forward relative to Covid-19 vaccines and Tonix’s programs in that area.

How do you view the Nation’s current vaccine strategies for COVID-19?

The U.S. started strong with Operation Warp Speed and got some great first-generation vaccines that gave us breathing room after the first wave of the COVID-19 pandemic.  But since then, we’ve squandered our advantage.  The US government stopped supporting development of any new vaccines at BARDA.  Now that the limitations of the mRNA vaccines have become apparent, we find we have lost more than a year.  We slept. The virus didn’t sleep.  Now we’ve got to catch up to the virus from behind.  And there’s a long road ahead.

At this point, many recognize that the current mRNA vaccines have two basic limitations – short durability of protection and an inability to block spread.  

Boosters Forever?

The mRNA vaccines don’t provide protection for more than 4-6 months.  That’s why already two successive “boosters” have been approved by the FDA.  That’s also why it’s likely that more boosters will be needed over time.  However, a top FDA official recently declared that a strategy based on endless boosters was untenable and not sustainable.  

We have also learned that mRNA vaccines do not prevent the spread of COVID-19.  We have learned that even vaccinated people pass infection with the delta and Omicron variants to others.  This is called forward transmission.  The inability of mRNA vaccines to block forward transmission is a big limitation.  History teaches us that slowing forward transmission is an important attribute of other vaccines that were successful in controlling viral diseases.  To use an analogy with forest fires, vaccination that blocks forward transmission is like wetting a forest to prevent spread of the fire. The mRNA vaccines are not wetting the forest.  They just protect tree by tree.

What about programs to tailor mRNA vaccines to specific variants?

There is more and more discussion about tailor-making new versions of mRNA vaccines that specifically address new variants like Omicron and BA.2. That will likely be tried because mRNA vaccines are easy to make and elicit strong antibody responses.  

But chasing each variant with a new tailor-made mRNA vaccine is a quick fix that sidesteps a fundamental technical limitation of mRNA vaccines.  At least in their current forms, mRNA vaccines have proven unable to evoke durable protective responses that most experts believe are the province of T cells, not antibodies. 

Much of the short-term protection mRNA vaccines provide comes from antibodies.  Antibodies are present in the blood for only about six months. What’s really needed for durable protection are vaccines that elicit T cell protection.  

T cells are known to protect against other viruses for years or decades.  Also, T cell protection is broader in terms of the variants.  T cells have been shown to recognize more variants than just the one that elicited it.  Antibody responses are more limited and protect against the variant or the vaccine that elicited it, but not other variants.

Chasing each variant with a new tailor-made mRNA vaccine may be untenable long term.  But near-term we are backed in a corner by the lack of other options, and it seems that FDA has appropriately endorsed the expedient fix at hand.  On the other hand, public health officials seem to be backing off proscriptive advice and seem to be pushing the decision about whether to get a second booster down to individuals, themselves.

Does this highlight the need for different types of vaccines, ones more geared to T cells?

It seems like there’s no time to lose in making vaccines that elicit strong T cell responses. The virus is not sleeping.  It has switched into a higher gear of mutating.  Now the virus is mutating using a process called recombination, which is basically how two variants have sex, since they swap genetic material. I fear this will rapidly accelerate the emergence of new variants.

That’s why we took a different approach – to develop a vaccine that would predominately stimulate T cell immunity. To do this we turned to live virus vaccine technology, which is one of the pillars of vaccine technology and, in fact, the oldest vaccine technology.  

Live virus vaccines were passed over in the first wave of COVID-19 vaccine development by Operation Warp Speed. Merck was developing two different live virus vaccines but stopped abruptly.  Live virus vaccines have longer development timelines than the mRNA, subunit and non-replicating technologies that were funded as part of Operation Warp Speed. 

What makes live virus technology a good fit for a COVID-19 vaccine? 

Live virus vaccines are the most successful vaccines ever developed, including those for smallpox, measles, mumps, rubella, chickenpox and several other viral infections. The most successful HIV vaccine trial was called the Thai Trial or RV144 run by the U.S. Army and that used a live virus vaccine. 

In these cases, live virus vaccines not only prevent illness, but also slow or block forward transmission. These live virus vaccines elicit durable, long-term immunity. They can be manufactured at scale with traditional techniques and processes. Live virus vaccines can be effective with a low dose, partly because they replicate in the arm. Finally, live virus vaccines typically require only standard refrigeration for shipping and storage.

Modern live virus vaccines don’t use live SARS-CoV-2 as a vaccine, but instead use a different virus, which in this context is called a viral vector.  The viral vector presents SARS-CoV-2 protein antigens to the immune system without exposing people to a living SARS-CoV-2 virus.

It is important that the viral vector has a known safety profile in humans.  The viral vector is engineered to express proteins from the pathogenic virus, and in the case of SARS-CoV-2 the most tested strategy so far has been to express the spike protein.  In this way, a modern live virus vaccine can be called a “sheep in wolf’s clothing”.  By that, I mean the vaccine itself has the safety profile of the viral vector, but the engineered vaccine alarms the immune system as if it was a dangerous SARS-CoV-2 virus.    

Merck won FDA approval for the first such live virus vaccine, rVSV-ZEBOV to protect against ebola.  The Merck vaccine is tame in terms of virulence, but to the immune system it looks enough like the dangerous ebola to elicit the immune response. Instead of exposing people to ebola itself or a weakened ebola virus, Merck uses a vesicular stomatitis virus (VSV) vector to expose the body to an ebola protein.  In the “sheep in wolf’s clothing” analogy, the VSV vector is the “sheep” and the ebola protein is the “wolf’s clothing”.

At Tonix, we have developed horsepox as the viral vector, which is the “sheep” in this analogy, and we have engineered it to express the spike protein from SARS-CoV-2 as the antigen, which is the “wolf’s clothing”.  The foundational work on this vector can be traced back to the 18th Century and the creation of the very first vaccine that led to the eradication of smallpox.  

But we are working on a very modern version called horsepox.  It wasn’t possible to make our vaccine until synthetic biology emerged as a new field.  A few years ago, making our vaccine was at the forefront of synthetic biology. We think that horsepox is still the largest virus ever synthesized. We believe horsepox is the most advanced form of a series of pox viral vectors, and that horsepox has capabilities beyond those of the canarypox vector that was used in the HIV vaccine Thai trial.

What's the status of your vaccine program?

We have shown that vaccinating monkeys with horsepox virus expressing SARS-CoV-2 spike protein elicited protective responses to the SARS-CoV-2 spike protein.  

Our goal in utilizing horsepox as a live virus vaccine vector is to develop a COVID-19 vaccine that is well tolerated, produces durable immunity, prevents forward transmission and can be rapidly and broadly deployed.

The first version of our COVID-19 vaccine, TNX-1800, encodes the spike protein from the original Wuhan strain of SARS-CoV-2, which is essentially the same protein used in the mRNA COVID-19 vaccines and most others in development. 

In animal testing of our TNX-1800 vaccine we found, after challenge with live SARS-CoV-2, vaccinated animals were protected, and that vaccination sterilized the upper airways. 

This feature seems relevant to slowing transmission of this airborne disease. If vaccination with TNX-1800 was able to slow the process by which infected people transmits the virus to others, it would be a capability that is not yet available in other vaccines. 

We are currently building the capabilities to vertically integrate development and manufacturing, and to package the product in multi-dose vials for shipping and storage with standard refrigeration. 

We are planning two new versions of the vaccine, TNX-1840 and TNX-1850, which encode the spike proteins from the Omicron and BA.2 strains, respectively.

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Seth Lederman, MD is the founder and CEO of Tonix Pharmaceuticals.  Prior to his career in biotechnology, Dr. Lederman served as a tenured professor at Columbia University where he conducted basic research in immunology and molecular virology.  

Important notice, please read: Certain statements in this document are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate,” “expect,” and “intend,” among others. These forward-looking statements are based on Tonix’s current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; delays and uncertainties caused by the global COVID-19 pandemic; risks related to the timing and progress of clinical development of our product candidates; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties; and substantial competition. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval, and commercialization of new products. Tonix does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2020, as filed with the Securities and Exchange Commission (the “SEC”) on March 15, 2021, and periodic reports filed with the SEC on or after the date thereof. All Tonix’s forward-looking statements are expressly qualified by all such risk factors and other cautionary statements. The information set forth herein speaks only as of the date thereof. This is not a solicitation of any offer to buy or sell. Redington, Inc. is paid by Tonix Pharmaceuticals Holding Corp. for investor relations services, and its employees or members of their families may from time to time own an equity interest in companies mentioned herein.

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