Will the spray vaccine change the new crown pandemic?

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“These types of new crown vaccines can help reduce individual infections and population transmission by directly activating the body’s first line of defense, mucosal immunity at the surface of the respiratory tract. Using them in combination with injectable vaccines produces more comprehensive immune protection.” Michael Ryan, head of WHO’s health emergency program, said in response to a reporter’s question at a news conference in Geneva, Switzerland, on Sept. 7 local time. The vaccine Ryan mentioned is the very same mucosal vaccine that is administered through the nose or mouth and is currently being developed by dozens of research teams and companies around the world.

Just before the meeting, two mucosal vaccines were approved in China and India. One of them, the inhaled adenovirus vector vaccine developed by China’s Kangxinuo Bio, Kvisa Mist U, was included as a booster shot by the State Drug Administration for emergency use on September 4. Two days later, a liquid nasal drip vaccine made by Bharat India received local approval for emergency use, primarily for unvaccinated individuals. Neither company has published data from phase III clinical trials.

The back-to-back approvals of these two mucosal vaccines sparked widespread interest in the industry, and on Sept. 6, Nature published an article titled “How Spray Vaccines Could Change the Pandemic.

“There is little difference in effectiveness between spray or inhalation vaccines, both of which are mucosal vaccines that are administered through the upper respiratory tract and stimulate the body to produce mucosal immunity.” Two mucosal vaccines were approved one after another, meaning an important step forward for the new crown vaccine, but there is still time to wait for the widespread use of such vaccines, Kim Dongyan, a virologist and professor at the University of Hong Kong School of Biomedical Sciences, told China Newsweek in an analysis.

More suitable as a booster shot

As of Sept. 17, more than 12.6 billion doses of the new crown vaccine had been administered worldwide, according to Oxford University. Although the vaccination rate is increasing, the cumulative number of infections continues to rise, and the cumulative number of infections worldwide has exceeded 600 million.

Most of the vaccines currently in use are intramuscular vaccines, which have a significant effect on preventing serious illness and death, but play a limited role in preventing infection, according to Jin Dongyan. The general intramuscular vaccine triggers an immune response when it enters the body, producing T cells that kill infected cells and B cells that produce neutralizing antibodies. These cells and antibodies circulate in the bloodstream, often touching the nose and respiratory tract by the time the infected person has developed symptoms.

“The enemy has evolved, and the world needs the next generation of vaccines to deal with it.” In a May 16 column in The New York Times, Akiko Iwasaki, a professor of immunology at Yale University School of Medicine, wrote that ideally, a vaccine could enter the mucus layer inside the nose to stimulate the body to produce antibodies that would strike the virus before it triggered symptoms. “It’s analogous to putting guards outside a house to patrol for intruders, rather than putting guards in the hallways of buildings and hoping they’ll catch the intruders,” she said by way of analogy.

Usually mucous membranes include the moist surfaces in the nasal, oral, genital or gastrointestinal tracts, which is where most pathogens enter the body and is also known as the body’s first line of defense. In the opinion of Dongyan Jin, intramuscular vaccines induce a systemic immune response, but do not stimulate mucosal immunity well and have a weak anti-infection effect. The local immune response induced by mucosal vaccines is similar to natural infection, and in theory, the anti-infection effect is better than that of intramuscular vaccines, but the induced systemic immune effect is weaker and more suitable for use as booster shots.

Some mucosal vaccines are the same as injectable vaccines, except that they have been changed to a droplet form of nasal spray, while some mucosal vaccines differ in composition or preparation process. Kvisa Mist U uses the same formulation ingredients as the injectable vaccine, but instead uses a nebulizer to nebulize the vaccine into tiny particles and completes the vaccination by oral inhalation, with each dose being only 1/5 of the intramuscular form, or 0.1 ml.

The main way to measure the efficacy of intramuscular vaccines is to measure the level of neutralizing antibodies in the blood, the higher the level the stronger the immune protection. Mucosal vaccines, on the other hand, lack a clear reference.

Bharat Biopharma India compares the serum neutralizing antibody levels measured in the nasal mucosal vaccine trial with those triggered by the intramuscular vaccine, but this makes it difficult to compare the true efficacy of the mucosal vaccine against infection. In July, a non-peer-reviewed study published on MedRxiv, a medical preprint platform, evaluated the immune efficacy and safety of the Concierto inhalation vaccine. In the study, 419 adult subjects who received two doses of inactivated vaccine were included in a low-dose nebulized group, a high-dose nebulized group and an inactivated group, with subjects in the first two groups inhaling 0.1 mL and 0.2 mL of the vaccine, respectively. The results showed that the inhalation booster produced higher antibody levels than those triggered by intramuscular vaccination.

“The company has conducted clinical trials of sequential immunization with inhaled Neocrown vaccine in tens of thousands of people.” On September 6, Consino Bio revealed in the interactive platform that a large amount of safety and immunogenicity data accumulated showed that the total number of adverse reactions such as headache, fatigue and fever decreased significantly in the inhaled vaccine, especially in the elderly; 28 days after sequential boosting with inhaled Neocrown vaccine, the cross-neutralizing antibody titer against live Omicron virus was 22.8 times higher.

In July, Concino said that the company had developed an inhaled vaccine that was effective against the New Guinea Omicron BA.1 mutant strain. However, the company has not yet conducted studies on the neutralization of the Omicron BA.4 and BA.5 variants.

Sun Jiayi, a postdoctoral fellow at Cornell University Medical College, told China Newsweek that inhalation vaccines could theoretically increase neutralizing antibody titers and locally induced antiviral immunity, allowing the virus to be neutralized at the first stage of entry into the body. However, most of these effects are still reflected in animal models, and no more evidence from large samples has been disclosed to prove that nasal spray vaccines are significantly better than ordinary inactivated vaccines in humans.

The latest data on “whether mucosal immunity protects against infection” were presented in a study published Sept. 14 in the New England Journal of Medicine by researchers at the Karolinska Institutet in Sweden. In the study, a total of 338 health care workers who received three doses of the vaccine were enrolled and followed up, and 57 of the subjects were infected with the new coronavirus during the follow-up period. The results showed high levels of serum antibodies in 99% of the subjects and mucosal immunoglobulin A antibodies in 62% of the subjects. High levels of immunoglobulin A antibodies reduced the risk of infection with omicron by more than half. “These findings suggest that mucosal antibodies in the respiratory tract help prevent infection with omicron. Further studies are still needed to confirm whether mucosal vaccines are more protective than intramuscular vaccines.” The researchers wrote in the paper. Notably, the study did not disclose specific information about the type of vaccine given to medical personnel for the three doses.

How long the immune response lasts is still unknown

“Despite the advantages of easy administration and triggering mucosal immunity with this type of new crown vaccine, and the fact that much research has been devoted to it, the application is not ideal and there are few success stories.” Lu Mengji, a German-Chinese virologist and professor at the Institute of Virus Research at the University of Essen Medical School, told China Newsweek that for a mucosal vaccine to achieve a breakthrough, it must first be clinically validated for vaccine effectiveness and second, it must have advantages over existing inactivated and mRNA vaccines, both of which have increased the difficulty of clinical trials for mucosal vaccines.

Mucosal vaccines against other viruses have been in development for decades, and there are currently at least nine mucosal vaccines approved for use in humans against pathogens such as poliovirus, influenza, and cholera. Eight of these are oral vaccines and one is a nasal spray vaccine for influenza.

“The oral polio vaccine contains attenuated poliovirus, which triggers an immune response in the host by infecting the gastrointestinal tract and is a typical example of a live attenuated and mucosal vaccine.” Such live attenuated vaccines can, in rare cases, mutate and cause disease in immune-deficient individuals, Jin Dongyan told China Newsweek. Live attenuated vaccines are not equivalent to mucosal vaccines, but many live attenuated vaccines are administered by oral or nasal spray and are also mucosal vaccines.

Jiang Qingwu, an epidemiologist and professor at the School of Public Health of Fudan University, told China Newsweek that in inhaled vaccines, for example, nebulized granular vaccines entering the body do not easily produce an effective immune response and are affected by the size and nature of the nebulized particles.

While intramuscular injections are more likely to deliver precise doses of the drug, nasal spray vaccines are difficult to do. This is because after entering the body, vaccine particles have to first pass through natural immune barriers like nasal hairs, the dense mucus layer of the airways, and are also affected by sneezing. As Akiko Iwasaki mentioned in the aforementioned New York Times op-ed, the mucus layer is an impenetrable barrier, and simply spraying a conventional vaccine up the nose can hardly produce a strong immune response. FluMist, a nasal vaccine for influenza currently approved in the U.S., stimulates an immune response by attenuating vaccine toxicity into nasal cells.

The nebulizer for the inhalation vaccine is a mechanically automated device that is relatively simple to operate and allows for accurate dosing down to 0.1 ml, and can maintain efficient immunity for at least six months after a single inhalation vaccination, staff at Concino Biologics told China Newsweek. “The entire process of nebulization is handled mechanically and automatically by the device, such as the size of the nebulized particles and the inhalation dose. There are strict production standards for the size of the nebulized particles to ensure effective activation of mucosal immunity.” The staff member said that this vaccine is only approved now and has not yet started to be used. Therefore it is uncertain where the nebulization device will be used. In the future, if the nasal spray or inhalation vaccine is administered by the people themselves, there are also issues related to how to ensure the effectiveness of the vaccination and how to upload and monitor the vaccination information.

Even if these barriers are cleared, past experience shows that nasal spray vaccines are not favored by the market. FluMist, for example, is the only nasal spray influenza vaccine on the market worldwide and has not sold well since its debut in 2003. The nasal spray flu vaccine is approved for healthy non-pregnant women aged 2 to 49 years, and is not recommended for people with certain medical conditions. And the older age group of 50 years and older makes up the largest share of the flu vaccine market. “The majority of flu vaccines currently on the market in the U.S. are still inactivated vaccines, as the nasal spray vaccine is riskier and less effective in specific populations.” Sun Jiayi said.

“The nasal spray flu vaccine will have a somewhat higher risk of side effects in the elderly,” Jin Dongyan said, adding that based on risk and other factors, the future nasal spray new crown vaccine may also be limited in terms of applicable population and age, for example, it should be used with caution for immune-deficient or immunocompromised people.

The antibodies produced in the nose are usually short-lived. “Many people may be more receptive to nasal sprays as opposed to needle injections. But the problem facing nasal vaccines now is how long the immunity lasts in the body.” In Akiko Iwasaki’s view, antibodies and memory immune cells have lasted only a few months in the nasal cavity in animal experiments so far. If this immunity wanes over time, it makes the most sense to use this type of vaccine as an over-the-counter type of booster every four to six months in response to a new crown pandemic.

Chen Xi, associate professor of global health policy and economics at Yale University, told China Newsweek that in the case of mucosal vaccines, although many companies are currently developing them, it is unlikely that such vaccines will substantially change the existing vaccine landscape if their effectiveness does not exceed that of existing mRNA vaccines.

Should be used in combination with injectable vaccines

In addition to mucosal vaccines, monovalent and bivalent vaccines against omicron are already on the market. “Some vaccines involving the BA.5 variant strain have been approved before clinical trials have been done. Some people have been immunized with these vaccines as a fourth dose for a booster.” Jin Dongyan said.

On Aug. 15, the British government approved a new generation of vaccines developed by Modena as boosters for mass vaccination. In each newly approved dose of Modena’s bivalent New Crown vaccine, the doses against the original New Crown strain and the Omicron strain are split in half, both at 25 micrograms, the U.K. Medicines and Healthcare products Regulatory Agency said in a statement the same day. Clinical trial data showed that the vaccine produced a “strong immune response” to both Omicron BA.1 and the original NIC virus, and also provided immune protection against the newly emerged Omicron BA.4/BA.5.

On August 22, Pfizer and BioNTech announced that they had applied to the U.S. Food and Drug Administration (FDA) for a booster dose of the experimental bivalent Neocon vaccine for people aged 12 years or older against the original Omicron strains as well as BA.4 and BA.5. Notably, there are no new human clinical trial data for the new booster vaccine; the license is based on mouse experiments and mRNA vaccine data used by drugmakers to date.

Other pharmaceutical companies, such as China’s Kexing and Sinopharm, are also launching research and development for a vaccine against Omicron and its subtype strains. Jin Dongyan understands that the previous clinical trial of a new generation monovalent inactivated vaccine conducted by HKU and Sinopharm is now nearing completion and will also apply for marketing approval in the near future.

According to Chen Xi, the current vaccine market is basically close to saturation, and under this circumstance, it is unknown how large the market can be won by the nasal spray vaccine when it enters the market in the future, and there are certain commercial risks. At the same time, the preparation technology of mRNA vaccines is relatively mature, and once a new mutant strain appears, it usually takes only a few days to adjust to the new mutant version of the vaccine. At present, on the other hand, nasal spray vaccines do not seem to be able to achieve this level of flexible response in terms of production technology.

In early September, the UK launched the fourth dose of the new crown vaccine program to prepare for a possible recurrence of the outbreak in the fall and winter. Meanwhile, a number of countries have launched or are in the process of launching booster vaccinations. Epidemic data show that the cumulative number of people infected in the United States is now about 100 million. “The actual number of infections is going to be much higher.” Chen Xi said many people around him have had their fourth dose of the vaccine, and as fall and winter approach, more people will get their fourth dose.

Christian Drosten, a leading German virologist, said in March this year that spraying the vaccine in the nose or throat is a way to stop the spread of the new crown.

Lu Mengji said that for the country, boosting vaccination is currently the easiest way to effectively deal with the outbreak, especially in places where medical conditions are weak. There could also be a large-scale spread of the epidemic this winter, and if vaccine coverage is relatively low, the impact on the elderly could be significant.

Several virologists told China Newsweek that the need for annual vaccination against the new crown in the future will depend on the killing power of the mutant strain. In Jin Dongyan’s opinion, both mRNA vaccines, inactivated vaccines, mucosal vaccines, and bivalent vaccines against omicron should be used to their advantage. Mucosal vaccines should be combined with other existing vaccines to maximize immunization and prevention as much as possible.