Researchers at the Department of Microbiology and State Key Laboratory of Emerging Infectious Diseases, LKS Faculty of Medicine of The University of Hong Kong (HKUMed) have conducted a comprehensive study for identifying an effective vaccine regimen in preventing SARS-CoV-2 nasal infection.
The study demonstrated that a combination of intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) prime and intranasal live attenuated influenza-based vaccine (LAIV-HK68-RBD) boost vaccination regimen induced the strongest mucosal broadly neutralizing antibodies and lung resident memory CD8 T cells, which prevented live SARS-CoV-2 nasal challenges in two animal models. The full research article is now online in the journal of EBioMedicine, published by The Lancet.
The COVID-19 pandemic has resulted in over 275 million of infections with nearly 5.36 million deaths by now, yet few vaccines approved for emergency use can induce sufficient mucosal protection for preventing robust SARS-CoV-2 nasal infection.
Although the current vaccination reduced rates of hospitalization, severity, and death significantly, these vaccines are much less effective in preventing SARS-CoV-2 respiratory transmission, which has posted great challenges for the pandemic control.
With continuous emergence of SARS-CoV-2 variants of concerns including the rapidly spreading of immune escape Omicron strain, it is urgent to discover a more effective vaccine strategy to block or reduce nasal transmission of SARS-CoV-2.
Research methods and findings
In this HKUMed study, substantially higher systemic and mucosal antibodies IgA/IgG and lung resident polyfunctional memory CD8 T cells were induced mainly by the heterologous combination regimen as compared with current COVID-19 vaccination regimens.
When two vaccinated mouse models were challenged at the memory phase, 35 days after the second vaccination, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous combination regimen besides consistent protection in lungs.
The new regimen-induced antibodies also cross-neutralized many pandemic variants of concern tested, including Alpha, Beta and Delta.
The findings provided the proof-of-concept that vaccine-induced robust mucosal immunity is necessary for preventing SARS-CoV-2 nasal infection, which has significant implication for ending the ongoing COVID-19 pandemic.
Significance of the study
“The findings suggested that the clinical development of our two HKU vaccines remains a top priority for eliminating the uncontrolled spread of COVID-19 pandemic. We are currently testing the influenza-based nasal spray vaccine and the DNA vaccine in humans,” remarked Professor Yuen Kwok-yung, Henry Fok Professor in Infectious Diseases and Chair of Infectious Diseases, Department of Microbiology, HKUMed, who is currently leading the clinical trials of these two vaccines in Hong Kong.
“The biggest challenge for our COVID-19 vaccine development is that we do not have a vaccine manufacturing plant in Hong Kong, which has delayed the translation of scientific discovery into clinical use.
Now, we face the same challenge after we have already made the Omicron-targeted DNA vaccine for timely clinical development,” said Professor Chen Zhiwei, Director of the AIDS Institute, Professor of Department of Microbiology, HKUMed, who co-led the research.
“We believe that using nasal spray vaccination to build up protection in the upper respiratory tract is the key strategy to reduce transmission of SARS-CoV-2 and important for the ultimate control of COVID-19 pandemic,” said Professor Chen Honglin, Professor of Department of Microbiology, HKUMed, who co-led the research.
COVID-19 entry portal
The main entry of SARS-CoV-2 occurs in the ciliated epithelium lining the nose [9–11]. The importance of the nasal epithelium in host invasion, involving the specific attachment of influenza and other viruses to the ciliated cells, was reported over 50 years ago . These ciliated cells have the highest expression levels, in the airways of the body, of the SARS-CoV-2 entry receptors, angiotensin converting enzyme 2 (ACE2), and the viral entry-associated protease, transmembrane serine protease 2 (TMPRSS2) [9–11].
SARS-CoV-2 binds to these using the receptor-binding domain (RBD) of the virus spike protein . Following attachment and entry into the nasal epithelium, the virus multiplies, spreading around the body . To emphasise, the ciliated cells of the nasal mucosa are the main host entry targets for the virus, so that denying access of SARS-CoV-2 to the entry receptors by intranasal drug prophylaxis needs prioritising.
New opportunities—Nasal therapy
Most SARS-CoV-2 vaccines are injected and mainly induce serum immunoglobulin G1 (IgG1), which enters and protects the lungs, leaving the nasal epithelia and upper respiratory tract largely unprotected. Any serum immunoglobulin A1 (IgA1) produced by vaccination is not effectively transported to the secretions of the upper respiratory tract including those of the nasal mucosa .
The dynamics of the mucosal immune response to COVID-19 is largely neglected, although the IgA secreted is 7 times more potent than IgG at neutralising SARS-CoV-2 [13–15]. Only natural infections induce both IgG1 to protect the lungs as well as IgA1 to protect the upper respiratory tract, including the nasal passages . Thus, injected vaccines fail to fully address the main portal of virus entry into the body through the nose, and, yet, few, if any, drugs have been developed to kill the virus in this early stage.
The nose is therefore likely to remain a source of infective virus transmission even after parenteral vaccination, which fails to completely eliminate the virus in the nose [1,17]. A single intranasal vaccination in rhesus macaques prevented SARS-CoV-2 infection in both the upper and lower respiratory tracts . Parenteral vaccination and nasal therapy combined could realise the ultimate goal of completely eliminating these viral pathogens and sterilising the nose.
Intranasal drug candidates
Drugs for nasal pharmacological prophylaxis against COVID-19 are under development and include (1) those blocking virus attachment to the host entry receptors without involving host immunity; and (2) intranasal vaccines or immune stimulants eliciting antiviral antibodies and memory cells at the mucosal surface.
- Category 1: Include povidone-iodine , nitric oxide , ethyl lauroyl arginate hydrochloride , astodrimer sodium (SPL7013) [22,23], iota-carrageenan [24–26], and many others. These utilise nasal sprays and are at different stages of development globally. One very significant study for prevention of the early phase of SARS-CoV-2 entry into the body utilises poly(lactic-co-glycolic acid) nanoparticles to deliver and confine drugs specifically to treat the nasal sinuses with slow release over one week . Stringent published clinical trials of these drugs are needed to satisfy the regulatory bodies as these may become available for sale to the public. Once approved, however, they could have enormous impacts on COVID-19 prophylaxis and therapy, particularly in deprived countries, as they are cheap and convenient and could also deal with breakthrough virus to sterilise the nose. They might be more acceptable too to those refusing injected vaccines.
- Category 2: Intranasal vaccines are also being developed, inducing IgA since dimeric forms of these antibodies are particularly potent and found at the mucosal surfaces where SARS-CoV-2 targets the cells .
Previous studies to develop nasal therapy for respiratory viruses have met with variable success. For example, a live attenuated flu nasal spray vaccine, called Flu Mist, has been approved by the US Food and Drug Administration (FDA), although the results of clinical trials have been discordant . Developing nasal sprays with some respiratory viruses can be problematic, epitomised by the common cold and the work of David Tyrell  who showed that more than 100 different viruses may be involved. SARS-CoV-2, however, is more promising since few variants dominate the pandemic and parenteral vaccines have already been produced. Preclinical and clinical trials with a variety of drugs for nasal therapy against COVID-19 are also underway.
For example, the nasal delivery of IgG monoclonal antibodies against SARS-CoV-2 engineered into immunoglobulin M (IgM) antibodies protect against virus variants in rats , while intranasal vaccination with the AstraZeneca vaccine, AZD1222, reduces virus concentrations in nasal swabs in 2 different SARS-CoV-2 animal models .
Furthermore, transgenic mice receiving one intranasal dose of an adenovirus-vectored vaccine, ChAd-SARS-CoV-2-S, also conferred superior immunity to SARS-CoV-2 than 2 intramuscular injections and evidenced sterilisation immunity in the upper respiratory tract . Additional progress has been made in India with the approval of a human Phase II clinical trial of a COVID-19 nasal vaccine .
There will inevitably be delays and setbacks due to our lack of understanding of the dynamics of intranasal vaccination for COVID-19 so that additional research is urgently required [14,34,35]. Meanwhile, some Category 1 drugs may be approved more rapidly and available to prevent viral shedding following full vaccination against Delta and other variants [23–25].
In conclusion, nasal therapy has great potential to prevent and treat a variety of respiratory viruses. As patients present at different stages of COVID-19 or with other viral infections, we will need a selection of therapeutic strategies from vaccines to broad-spectrum antiviral drugs, delivered in different ways from injection, sprays/inhalations, and tablets alone or in combinations, to counter these threats.
referenc elink :https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010079
More information: Runhong Zhou et al, Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination in mouse models, EBioMedicine (2021). DOI: 10.1016/j.ebiom.2021.103762