Engineered Nanobodies Show Promise in Preventing COVID-19: Study
Sun, April 18, 2021

Engineered Nanobodies Show Promise in Preventing COVID-19: Study


A team of scientists developed an inhalable protection against COVID-19. This could be deployed as the world waits for a safe and effective vaccine.

The innovative protection against COVID-19 was developed by scientists at the University of California-San Francisco (UCSF), a US public research university. They called it AeroNabs that could be aerosolized and administered as an inhaler or nasal spray. Its once-a-day administration could provide robust and reliable protection against the disease. Its product design was intended to commercialize a low-cost, over-the-counter (OTC) medication for COVID-19. They published their findings in the journal bioRxiv.

The Desperate Need for a COVID-19 Vaccine

According to the 205th Situation Report of the World Health Organization (WHO) of the United Nations, 20,162,474 confirmed cases and 737,417 confirmed deaths due to COVID-19 worldwide were reported across six regions, as of August 12, 2020. The Region of the Americas reported the highest confirmed cases at 10,799,062 and confirmed deaths at 393,727. The WHO expressed concern on the rising death toll of COVID-19 in the Americas.

The almost 400,000 deaths can threaten plans related to eliminating or controlling other infectious diseases, such as HIV, hepatitis, and tuberculosis. Many of these diseases have no cure and are excellent coinfection candidates. If those plans are impaired, coinfection of COVID-19 and any of other disease will further spike death count in the Americas.

Despite doubts cast on the Russian vaccine approval, many hopes that it can effectively treat or prevent COVID-19. Even if it can only provide partial protection, it will give some respite to frontliners, particularly healthcare workers who have not taken rest in this war. The world is also expecting newer treatments to be developed soon. These will be used to treat patients to effectively stop community transmission.



Nanobodies Show Promise against COVID-19

At UCSF, scientists developed a potential treatment for the disease. It could be administered via an inhaler or nasal spray to protect people from SARS-CoV-2. However, it would not replace any effective vaccine against COVID-19. As of the moment, active discussions with commercial partners were being performed to push clinical testing and manufacturing of the product. It has been planned to place an inexpensive, OTC drug in the market.

“Far more effective than wearable forms of personal protective equipment, we think of AeroNabs as a molecular form of PPE that could serve as an important stopgap until vaccines provide a more permanent solution to COVID-19,” said Dr. Peter Walter, co-inventor and professor of biochemistry and biophysics at UCSF.

Scientists designed and developed the product with the inspiration of nanobodies: antibody-like immune proteins found in camels, llamas, and related animals. Although nanobodies exhibited many similarities with antibodies, the former had more to offer including effective against SARS-CoV-2 and simple structure. Nanobodies could be modified easily and be manufactured massively at lower prices than antibodies.

To utilize nanobodies as a COVID-19 treatment, scientists had to make sure the proteins would work against the coronavirus. So, they looked into co-inventor Aashish Manglik’s library of more than 2 billion synthetic nanobodies. They performed a series of tests to determine which nanobodies could bind to the spike protein of SARS-CoV-2. The tests also revealed which nanobodies had the best and worst effectiveness. The tests yielded 21 nanobody candidates that could bind to the spike protein. The candidates prevented a modified form of the spike protein from interacting with ACE2, the receptor the coronavirus requires.

Additional experiments, including cryo-electron microscopy, were performed to better see the interface of nanobodies and spike proteins. Nanobodies showed robust blocking in the spike's RBDs or receptor-binding domains. Nanobodies acted like sheaths of swords or in this case, sheaths of the RBD’s key to forbid connection to ACE2’s lock. Their actions canceled the lock-and-key mechanism of SARS-CoV-2.

To know if the candidates could work in real-world settings, scientists prepared new experiments involving the real SARS-CoV-2 virus. They tested three of the most promising nanobodies against the coronavirus. They observed that the nanobodies could protect cells from being infected. Results showed the extraordinary potency of the three nanobodies even at very low doses.

Among three extraordinary nanobodies, one was found with exquisite extra function. This nanobody acted as sheathe and mousetrap at the same time. It would clamp down on the spike protein to further prevent interaction with ACE2. But how did the team managed to turn nanobodies into a treatment?



The Creation of AeroNabs

Scientists needed to optimize nanobodies to formulate a treatment. For that, they engineered the most potent nanobody they discovered. Multiple experiments were conducted to optimize it for product development. One experiment involved mutating every one of the amino-acid building blocks of the nanobody, which contacts the spike protein. This resulted in two changes that upgraded the potency by 500 times.

But in another experiment, a molecular chain was engineered to connect three nanobodies together. Since each spike protein of the coronavirus possessed three RBDs, it could easily attach to ACE2 receptor. The combination of three nanobodies could disable all three RBDs. Once a connection to a single RBD was made, the remaining two would be attached as well. This engineered version was 200,000 times better than one nanobody.

The most recent prototype of AeroNabs was confirmed stable. It would not lose potency even if aerosolized. The formula endured multiple stress tests, such as high temperatures and conversion to shelf-stable powders. The nanobodies remained stable across all stress tests performed, compared to antibodies.

The nanobodies could be delivered through aerosolization using specific devices. The molecules in aerosols could be self-administered and its protective effect could last for 24 hours. But its intended application is for preventing or treating COVID-19. It could be integrated into existing protocols or upcoming vaccines.

At the moment, scientists are having conversations with entities interested in supporting their project. The support will help the product reach manufacturing and clinical testing stages. If the tests yield positive results, they can aim for regulatory approval to reach the commercial market. They are yet to reveal the price of the product.