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With 13 COVID-19 vaccines in use around the world, pharmaceutical companies are exploring second-generation technology that could change the way doses are administered and distributed.

These vaccines can be taken orally as a capsule that can be swallowed, as a tablet that dissolves under the tongue, or as a nasal spray. Such formulations would not require refrigeration and would not need healthcare personnel to administer them.

The efforts are in their early stages with no guarantee of success. Research and development costs are high, and only a small number of companies – none with a vaccine currently licensed for use – are exploring these alternative methods. Work may seem like a gamble, but could play a vital role in ending the pandemic.

“It’s encouraging to see manufacturers looking for easier-to-administer formulations of the vaccine,” said Esther Krofah, executive director of Milken Institute’s FasterCures. “We need to have a global focus, and not just a national focus.”

With 22% of its population vaccinated, the United States has administered more doses than any other country in the world, and data shows that high-income countries delivered doses more effectively than low-income countries.

“The United States cannot be safe if the rest of the world is not safe,” said Bruce Innis of PATH, a non-profit organization working in 70 countries to ensure global equity in human rights. health care. “At a time in the country where the prism of fairness applies to everything, we may not feel good about getting the vaccine if it is not happening everywhere.”

Current vaccines require syringes and refrigeration. These requirements present logistical challenges if the SARS-Cov-2 virus is to be eradicated.

Moderna and Pfizer vaccines require ultra-cold storage or dry ice. The Johnson & Johnson vaccine, which has been on hold while authorities investigate reports of very rare but dangerous blood clots, can be stored at temperatures just above freezing.

According to FasterCures, which tracks 326 COVID-19 treatments and 252 vaccines, five companies are developing oral vaccines and two – ImmunityBio and Vaxart – have progressed to Phase 1 clinical trials.

Thirteen companies are working on intranasal sprays and five are in early clinical trials.

“We should not underestimate how difficult it is to create the right vaccine formulations that will generate an effective immune response,” Krofah said.

Dr William Schaffner, an infectious disease expert at Vanderbilt University and medical director of the National Foundation for Infectious Diseases, said he was impressed that two companies are in Phase 1 trials.

“People have been looking to create an oral vaccine for a long time without much success,” Schaffner said. “It’s exciting, new and distinctive.”

Other experts take a wait-and-see approach.

“Phase 1 is a long way from having a product,” Dr. Paul Offit, of the Children’s Hospital of Philadelphia, said in an email, adding that the FDA had no problem approving the first studies.

“I would be careful if it goes from phase 1 to phase 2 and goes to phase 3,” said Dr. Kelly Moore, deputy director of the Immunization Action Coalition, a nonprofit that provides information on vaccines and their distribution. “Many good ideas fall between phase 1 and phase 2 and even more do not make it into phase 3.”

In February, the Food and Drug Administration approved the expansion of a Phase 1 clinical trial by ImmunityBio to include two more versions of its COVID-19 vaccine: a capsule that can be swallowed and a tablet that dissolves under the tongue. . The company has been testing the injectable version of its vaccine for six months. The tests are administered by Hoag Hospital in Newport Beach and have gone from 35 to 140 participants.

El Segundo-based ImmunityBio is the only company to simultaneously test injectable and oral versions of its vaccine, according to data from FasterCures. ImmunityBio President and CEO Dr. Patrick Soon-Shiong also owns The Times.

The vaccine developed by ImmunityBio is different from the vaccines developed by Moderna, Pfizer and Johnson & Johnson. These vaccines induce the immune system to generate antibodies against the virus spike protein. The ImmunityBio vaccine, however, is designed to induce antibodies not only against the spike protein outside the virus, but also against a different protein inside the virus.

Because the internal protein is less likely to mutate than the spike protein, the vaccine could potentially be more effective against the coronavirus variants, experts say.

“My concept of an ideal vaccine,” Soon-Shiong said, “is one that does not need refrigeration, provides quadruple immunity with antibodies, T cells, mucosal protection and long-term memory. , and most importantly, protects against the variants that are emerging now.

Last week, ImmunityBio released preliminary results from the Phase 1 trial of its injectable vaccine, which showed a “tenfold increase” in T cell response – a key immunological response – among trial participants. , compared to infected people. with the virus.

South San Francisco-based biotechnology company Vaxart began Phase 1 clinical trials for an oral COVID-19 vaccine in the fall.

Preliminary results released in February indicated that although his vaccine did not produce neutralizing antibodies, “we have seen fantastic T cell responses,” said Dr Sean Tucker, founder and scientific director of Vaxart.

“The profile of a tablet vaccine is compelling,” Tucker said, citing its stability at room temperature and the fact that it is easy to carry and swallow and does not need needles to administer. . “However, it was just difficult to get the oral vaccination to work. Usually, the vaccine is broken down like food. ”

Oral polio vaccine – a benchmark of success – took almost 10 years to develop. First introduced as an injectable vaccine by Jonas Salk in 1953, the oral version, formulated by Albert Sabin, appeared in 1962. The near eradication of polio worldwide is largely attributed to the convenience of a vaccine. oral.

But the poliovirus is a different type of virus from the new coronavirus. They are both equally contagious, but a polio infection begins in the digestive tract before reaching the nervous system and causing paralysis. An oral polio vaccine targets the initial site of infection.

Oral vaccines have also been effective against rotavirus and salmonella, but according to Dr Buddy Creech, director of the vaccine research program at Vanderbilt University Medical Center, the challenge is to ensure that a sufficient amount of vaccine survives. in the stomach to trigger an immune system. reply.

As a respiratory disease, the new coronavirus is similar to the flu, and although the flu vaccine is usually given by injection into the arm, one company has developed an intranasal version. FluMist is an aerosol spray that targets the nose and throat where infection with the virus often begins. FluMist, Creech said, produces a comparable and, in some ways, better immune response than an injected vaccine.

The methods of administering a vaccine are not the only obstacle to greater global distribution. Pfizer and Moderna vaccines should be stored at minus 94 degrees Fahrenheit, and Johnson & Johnson vaccine should be stored between 36 and 46 degrees Fahrenheit.

Pfizer is developing a powdered version of its vaccine, according to a company spokesperson. Essentially lyophilized, a vaccine in this form is more stable than a liquid vaccine, and its storage requirements are comparable to those of the Johnson & Johnson vaccine.

Once there, the Pfizer vaccine would be reconstituted in liquid form and injected. It is also being reformulated to require one hit. Clinical trials on this version of their injectable vaccine have not yet started.

Finding an alternate method of delivering the vaccine is a “huge investment,” said Moore of the Immunization Action Coalition, which is why most companies avoid it, and for companies that don’t. have yet to produce a viable vaccine, that’s a gamble.

“Convenience doesn’t make sense if the vaccine itself doesn’t work,” said Dr. Lawrence Steinman, an immunologist and neurologist at Stanford University.

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