A team led by Alexander Douglas from the University of Oxford reported disappointing results from the phase 1 trial for the intranasal administration of the ChAdOx1 vaccine against Covid-19. Consisting of a replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike protein, the vaccine is usually administered intramuscularly and has been shown to prevent severe disease and death. but none of las vaccines current ha Dyed and It issuccess similar in the blocking of the transmission viral.
Vaccines administered into the nasal mucosa could potentially prevent SARS-CoV-2 infection at the point of viral entry into the respiratory tract, stopping the spread of the virus. We urgently need more research to develop vaccines that can block the transmission of respiratory pandemic viruses using delivery routes that are safe and practical on a large scale.
There is much to break down in the article on intranasal ChAdOx1 published by Douglas et al in eBiomedicine. Although the study enrolled only 42 participants, it included a mosaic of different treatment groups.
The 30 participants who had not received a prior vaccine were divided into three groups that received different doses. Those three naive groups were further subdivided, with 14 participants scheduled to receive an intranasal booster 28 days later. The remaining trial participants had previously been vaccinated with two intramuscular doses of either ChAdOx1 or BNT162b2 (Pfizer/BioNTech mRNA vaccine), and all received the higher intranasal dose as a booster.
The primary objective of this single-site, open-label study was to assess the safety and tolerability of intranasal vaccination, and this objective was met, with the most common side effects being sore throat, runny nose, headache, and nausea. fatigue. The secondary objective of the study was to assess immunogenicity by measuring serum and mucosal antibody responses to the SARS-CoV-2 spike protein.
Unfortunately, only a small fraction of previously unvaccinated participants showed a substantial induction of mucosal immunoglobulin A (IgA) or IgG directed against the spike protein after the first nasal vaccination, regardless of dose. Serum IgG and IgA responses were also infrequent and of low magnitude.
Analysis of the data on the boost given on day 28 was complicated by a major confounding factor: 12 participants received, outside of the study, mRNA vaccine injections after taking the first intranasal dose of ChAdOx1; 11 of these had substantial levels mucosal anti-spike IgG, and 5 showed induction of a mucosal IgA response (no antibody data provided for the 12th participant). However, most of the remaining members of the naïve groups who received two intranasal doses of ChAdOx1 did not develop IgA or IgG responses in the nasal mucosa.
Similarly, the nasal boost of ChAdOx1 failed to induce strong mucosal antibody responses in the majority of the 12 previously vaccinated participants. To top it off, 7 members of the intranasal mid-dose and high-dose groups developed symptomatic COVID-19 during the trial period, although none required hospitalization. Therefore, despite meeting its primary safety endpoint, the study will not proceed to Phase 2.
A recent survey of nasal COVID-19 vaccine candidates published in Nature had more than 100 in development and 20 in clinical trials. In early September 2022, CanSino Biologics announced that China’s National Medical Products Administration had approved an orally inhaled version of its Convidia, which uses a type 5 adenovirus vector encoding the SARS-CoV spike protein. -2, as a booster, and is now being administered in Shanghai. CanSino published the results of a 420-participant trial showing that in people previously vaccinated with two intramuscular doses of CoronaVac (Sinovac’s inactivated SARS-CoV-2 vaccine), one dose of nebulized Convidia induced neutralizing serum antibody responses plus stronger than those induced by a third intramuscular dose of CoronaVac.
A nasal spray vaccine, Bharat Biotech’s iNCOVACC, was also recently approved by India’s Central Drug Standards Control Organization. The company submitted test data to regulators, but has not released the results yet.
Intranasal administration of ChAdOx1 had shown excellent results in hamsters and rhesus macaques, both in terms of immunogenicity and protection against SARS-CoV-2 infection. At least one other intranasal COVID-19 vaccine has been discontinued after phase 1 results showed good safety data but low immunogenicity: Altimmune’s AdCOVID, a nasal spray formulation of its type 5 adenovirus vector encoding the domain of binding to the SARS-CoV-2 spike receptor. Altimmune had also reported strong preclinical data.
It is resounding failure of the vaccination intranasal for induce answers immune mucous membranes o sistIt ismicas in humans afterIt iss of results clearly positives in mice, there ismsters y primates no humans, highlights the need of develop models preclinunique more solid for the immunology mucosal.
It is also important to note that Convidecia and iNCOVACC were approved by regulators on the basis of inducing antibody responses to the spike protein. More needs to be known about the correlates of protection in mucosal immunity to understand how, or even if, this will affect infection and transmission.
Both natural SARS-CoV-2 infection and intramuscular vaccination have been shown to elicit IgA responses, and it is unclear how they affect reinfection rates. Of course, there are other valid reasons for developing intranasal vaccines, including their ease of administration and the need to reach people with a fear of needles. But those hoping intranasal vaccines will break SARS-CoV-2 transmission chains may have to wait for the countryside to find its “second wind.”
Ronald Palacios Castrillo, MD, PhD.
