Assessing an intranasal lentiviral booster against COVID-19 variants

By Dr. Shital Sarah Ahaley Ph.DFeb 2 2022Reviewed by Aimee Molineux

Coronavirus disease 2019 (COVID-19) vaccines provide adaptive immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the emergence of new SARS-CoV-2 variants, vaccine waning with time is a concern.

A new study explores the possibility of vaccination via nasal route utilizing a lentiviral vaccination vector (LV) to be administered as a booster dose.

A preprint version of the study, which is yet to undergo peer review, is available on the bioRxiv* server.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Previous studies

A non-integrative LV encoding the full-length sequence of Spike glycoprotein (S) from the wild-type SARS-CoV-2 (LV::S) has been constructed previously. LV::S vaccine injected as a first dose followed by intranasal (i.n.) boost has shown promising results in multiple preclinical animal models. LV::S protects the respiratory tract against all SARS-CoV-2 variants.

Human Angiotensin-Converting Enzyme 2 (hACE2) expressing transgenic mice permit SARS-CoV-2 replication in the brain. An i.n. boost with LV::S protects the central nervous system in these mice.

LV vaccine

LVs do not integrate into the host. They do not replicate, cause changes in the host cell, or cause inflammation. These vectors are designed with a different glycoprotein on their surface due to which they can infect different types of cells, including the antigen-presenting cells of the immune system. This allows efficient activation of the immune system.

Importantly, it allows the LVs to avoid the targets of preexisting vaccine-induced immunity in humans.

The safety of LV vaccines has been demonstrated in humans in a phase I/IIa Human Immunodeficiency Virus-1 therapeutic vaccine trial. However, this study used an integrative version of LV.

LVs are good candidates for mucosal vaccination. The i.n. vaccination approach is expected to trigger immune cells in the respiratory tract allowing virus neutralization at the point of entry before it reaches the lungs and other organs. The i.n. route is most effective in reducing SARS-CoV-2 transmission in hamster and macaque preclinical models.

Furthermore, LV::S is suitable as a heterologous i.n. booster vaccine, to reinforce and broaden protection against the emerging variants, particularly in early vaccinated nations where vaccine waning is observed and infections are on the rise.

Preclinical study in mice

This study lays the foundation for a clinical trial. LV::S_Beta-2P was generated using the S protein of the SARS-CoV-2 Beta variant. In this study, mice were administered with two intramuscular (i.m.) doses of mRNA vaccine encoding the wild-type S protein. The immunity in these mice was waning with time. Four months post-vaccination, the mice were administered an i.n. LV::S_Beta-2P heterologous boost and the immune responses and protective potential were investigated.

LV::S_Beta-2P i.n. booster

Full-length S proteins from the Alpha, Beta, and Gamma SARS-CoV-2 variants of concern (VOCs) were tested to assess the neutralization breadth. The S_Beta-2P was the best cross-reactive antigen among all the candidates tested for antigen design. S_Beta-2P was capable of neutralizing all the other variants.

Mice vaccinated with two doses of an mRNA vaccine, with waning immunity at 4 months post-vaccination, were administered an i.n. boost with LV::S_Beta-2P. There was a dose-dependent increase in the cross-neutralizing antibody levels and in the immune cells. This boost was observed at the lung cellular level.

The mucosal anti-Spike IgG and IgA, lung resident B cells, and effector memory and resident T cells were efficiently induced after the i.n. boost.

The lungs of the mice did not show specific immune infiltration or syndrome.

The mice could be infected with the Delta variant only four months after the two doses of the mRNA vaccine, i.e. there was less protection offered by the vaccine with time. A LV::S_Beta-2P heterologous i.n. boost, given at week 15 after the first injection of mRNA, provided complete protection against a high dose of the SARS-CoV-2 Delta variant. There was no viral replication in 100% of the animals tested. Thus, the lungs were completely protected against the SARS-CoV-2 Delta variant.

Implications of the study

Vaccine waning has been observed in the COVID-19 pandemic, especially against VOCs. Due to this, additional booster doses are recommended. A combination of vaccine platforms, with the first dose of one vaccine and a second dose of another vaccine, could be more efficient for long-term protection.

The LV-based strategy is highly efficient in inducing different types of immune responses. Moreover, it can be administered as an i.n. boost.

The LV::S_Beta-2P i.n. boost strengthens the immunity, cross-recognizes VOCs, and targets immune cell responses to the respiratory tract, the main entry point of SARS-CoV-2. This also avoids infection of the lungs and other organs. Thus, the LV::S_Beta-2P vaccine is a promising candidate as an i.n. booster against COVID-19.

This study has paved the way for a phase I clinical trial for the use of i.n. boost by LV::S_Beta-2P in previously vaccinated humans or COVID-19 convalescents.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources