Nasal administration of COVID-19 vaccine

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Researchers lead by Professor Michael S. Diamond at Washington University School of Medicine in St. Louis, have developed a COVID-19 vaccine delivered via the nose that was found to protect mice from the SARS-CoV-2 virus. In Figure 1 is depicted, how mouse lung tissue looks when infected with SARS-CoV-2?

On the left hand side we see lung tissue from a mouse that received a control vaccine with no protective effects. It shows a large number of dense colored inflammatory cells. On the right of the picture is lung tissue from a mouse that received a nasal vaccine encoding the virus’ spike protein. The vaccine protected against infection, and large numbers of inflammatory cells are absent.

Figure 1. Microscopic picutres of SARS-CoV-2 virus-infected lung tissue [1]. Left: treated with control vaccine, right : treated with vaccine encoding the virus’ spike protein

Unlike other COVID-19 vaccines in development, this one is delivered via the nose, where most initial infections occur. In the new study, the researchers found that the nasal delivery route created a strong immune response throughout the entire body, but it was particularly effective in the nose and respiratory tract, preventing the infection from taking hold in the body.

“We were happily surprised to see a strong immune response in the cells of the inner lining of the nose and upper airway — and a profound protection from infection with this virus,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and a professor of molecular microbiology, and of pathology and immunology. “These mice were well protected from disease. And in some of the mice, we saw evidence of sterilizing immunity, where there is no sign of infection whatsoever after the mouse is challenged with the virus.”

How was this new vaccine contructed?

The new construct was made by inserting the spike protein of the SARS-CoV-2, inside another virus – a chimpanzee adenovirus – that causes the common cold. But the scientists tweaked the adenovirus, rendering it safe, unable to cause any disease. The harmless adenovirus carries the spike protein into the nose, enabling the body to build an immune defense against the SARS-CoV-2 virus without becoming sick.

Another creative innovation beyond nasal delivery is that the new vaccine incorporates two mutations into the spike protein. These mutations stabilize it in such a specific shape which is most conducive to forming antibodies against it.

“Adenoviruses are the basis for many investigational vaccines for COVID-19 and other infectious diseases, such as Ebola virus and tuberculosis, and they have good safety and efficacy records, but not much research has been done with nasal delivery of these vaccines,” said co-senior author David T. Curiel, MD, PhD, the Distinguished Professor of Radiation Oncology. “All of the other adenovirus vaccines in development for COVID-19 are delivered by injection into the arm or thigh muscle. The nose is a novel route, so our results are surprising and promising. It’s also important that a single dose produced such a robust immune response. Vaccines that require two doses for full protection are less effective because some people, for various reasons, never receive the second dose.”

Although there is an influenza vaccine called FluMist™ (See Figure 2 ) that is delivered through the nose, it uses a weakened form of the live influenza virus and can’t be administered to certain groups, including those whose immune systems are compromised by illnesses such as cancer, diabetes or HIV. In contrast, the new COVID-19 intranasal vaccine in this study does not use a live virus capable of replication, presumably making it safer.

Figure 2 FluMist Quadrivalent intranasal Vaccine by MedImmune

The researchers compared this vaccine administered to the mice in two ways — in the nose and through intramuscular injection. While the injection induced an immune response that prevented pneumonia, it did not prevent infection in the nose and lungs. Such a vaccine might reduce the severity of COVID-19, but it would not totally block infection or prevent infected individuals from spreading the virus.

In contrast, the nasal delivery route prevented infection in both the upper and lower respiratory tract — the nose and lungs — suggesting that vaccinated individuals would not spread the virus or develop infections elsewhere in the body.

The study is highly promising but cautioned that the vaccine so far has only been studied in mice. Further investigations will follow to test this intranasal vaccine in nonhuman primates with a plan to move into human clinical trials as quickly as possible. Based on the above animal study results, authors suggest that intranasal delivery of ChAd-SARS-CoV-2-S vaccine is a promising platform for preventing SARS-CoV-2 infection, disease, and upper airway transmission and thus warrants clinical evaluation in humans.

More details of this study have just been published in the prestigious journal:

A.O Hassan et al Cell 183, 169–184, October 1, 2020.

Some examples on the utility of cyclodextrins in nasal vaccines

PCT patent application discloses intranasal vaccine compositions containing Yersinia pestis bacterial antigens with cyclodextrin derivatives and other adjuvant chemicals, such as stabilizers, surfactants, complexing agents, etc. [2] Mice were intranasally immunized with admixed F1 (5mg) and V (1mg) antigens of Yersinia pestis in conjunction with 2.5% cyclodextrin. Serum was analyzed on the day 14 for the presence of relevant antibodies. The composition showed significant absorption enhancer effects as compared to the controls. The composition according to this invention can be either sprayable solution or solid particles such as microspheres or liposomes, particularly useful for mucosal administration of vaccines, for the intra-nasal route or by parenteral routes.

Another invention filed by Sanofi Pasteur [3] is directed to an immunogenic composition comprising at least one inactivated poliovirus (IPV) serotype and at least one cyclodextrin or derivative thereof. The immunogenic composition according to te main claim, contains γ-cyclodextrin, β-cyclodextrin, C1-C3 hydroxyalkyl derivatives of γ-cyclodextrin or β-cyclodextrin, glycoside derivatives of γ -cyclodextrin or β-cyclodextrin, and a mixture thereof, and preferably amongst γ -cyclodextrin, 2- hydroxypropyl γ -cyclodextrin and a mixture thereof. The invention also concerns said immunogenic composition for use as a vaccine as well as the use of a cyclodextrins, to protect the inactivated polyovirus IPV immunogenicity in presence of thiomersal preservative. The invention is also directed to a method of preparing a vaccine composition and to a method of immunizing a host against poliomyelitis.

Japanese researchers published on a cyclodextrin-enabled influenza vaccine suitable for mucosal, mainly for nasal vaccine delivery. [4] Intranasal vaccination with inactivated influenza viral antigens could be an attractive, patient friendly alternative to currently available influenza (flu) vaccines. In this study Kusakabe and co-authors examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), can act as a mucosal adjuvant for intranasal flu vaccines. It was found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virus influenza virus with HP-β-CD resulted in secretion of vaccine-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. It is noteworthy that intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant and replacer of aluminum salt, for seasonal and pandemic influenza vaccines.

[1] Ahmed O. Hassan et al. A Single-Dose Intranasal ChAd Vaccine Protects Upper and Lower Respiratory Tracts against SARSCoV-2. Cell 183, 169–184, October 1, 2020.

[2] Oya et al. Vaccine composition. PCT Int. Appl. WO 2000056361, 2000

[3] Chacornac, I. et al. Vaccine composition comprising IPV and cyclodextrin. PCT Pat. Appl. WO2016012385, 2016

[4] Kusakabe, T. et al Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection. Vaccine 34 (2016)

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