In a preprint on BioRxiv, scientists from the Pasteur-TheraVectys joint lab have disseminated animal test results for an intranasal, lentiviral vector-based COVID-19 vaccine. This study demonstrates that the vaccine candidate induces very high antibody production and strong cell-mediated response, while also drastically reducing lung viral loads. This work proves that an efficacious vaccine for SARS-CoV-2 must provide vaccine protection in the upper respiratory tract through which the virus enters the body.
"In order to be effective, a coronavirus vaccine must provide protection at the site where the virus enters the body, namely the respiratory tract. Neutralizing antibodies present in the blood actually only contribute minimally to protection. Our vaccine candidate drastically reduces lung viral loads (by a factor of 100,000)".
Pierre Charneau, Head of the Institut Pasteur Molecular Virology and Vaccinology Unit, Chief Scientific Officer of TheraVectys, Head of the two entities' Joint Lab.
The vaccination strategy developed in this study is based on a lentiviral vaccine vector, and therefore uses a non-replicative viral vector. An initial injection of a vector expressing the SARS-CoV-2 Spike protein triggered very high antibody titers in mouse serum with an in vitro neutralization capacity comparable to that of symptomatic human patients recovered from COVID-19.
High numbers of specific T cells (cell-mediated immunity) were also induced in vaccinated animals. Despite the intense neutralizing activity measured in the blood, only moderate protection was observed after SARS-CoV2 challenge, with lung viral loads only reduced by a factor of approximately 10.
However, a parallel study demonstrated that IgA-type antibodies present in the lung mucosa were much more useful for neutralizing the virus than IgG antibodies present in the blood.
A prime and target vaccination regimen was therefore applied, in which the immune response was initiated by a standard intramuscular injection, and then targeted in the upper respiratory tract through intranasal instillation of the vaccine.
When this prime and target vaccination strategy was used, neutralizing activity measured in the blood did not increase substantially. However, a significant effect on protection was observed after challenge, with lung viral load reduced by a factor of 100,000, falling below the detection limit of an RT-PCR assay in some animals. Due to the high level of protection achieved, pulmonary inflammation and cytokine storm were completely inhibited, thus preventing lung tissue lesions.
"This work introduces the important notion that neutralization activity measured in serum is probably not correlated to the level of protection, and that vaccine protection against SARS-CoV-2 requires specific immunity, notably from IgA antibodies, at the site at which the virus enters the body, namely the upper respiratory tract," explains Laleh Majlessi, co-author of the study and head of research at the Pasteur/TheraVectys joint lab.
This study on mice was confirmed in the hamster model, an animal that naturally mirrors COVID-19 human pathophysiology, and as such, is highly predictive of vaccine efficacy in humans. Once again, the prime and target vaccination strategy induced very strong protection with a major reduction in lung viral loads after SARS-CoV-2 challenge and very significant inhibition of pulmonary inflammation, cytokine storm, and tissue lesions.
Given the main target population for the SARS-CoV-2 vaccine is elderly people, convincing protection in preclinical models is essential for subsequent development. The duration of induced protection is a further important criterion. Although by definition, these ongoing tests take time, long-standing protection has already been demonstrated with the lentiviral vaccine platform in several vaccines previously developed for SIV (in Macaca monkeys), Zika virus, West Nile virus, and therapeutic antitumoral vaccines.
This COVID-19 vaccine was developed after the same team from the Pasteur-TheraVectys joint lab under Dr. Pierre Charneau's scientific supervision developed the first sero-neutralization assay, named Lenti.S.
 IgA dominates the early neutralizing antibody response to SARS-CoV-2, sous presse dans Science Translational Medicine
Intranasal Immunization with a Lentiviral Vector Coding for SARS-CoV-2 Spike Protein Confers Vigorous Protection in Pre-Clinical Animal Models, BioRxiv, July 24, 2020
Min-Wen Ku1£, Maryline Bourgine1,2£, Pierre Authié1£, Jodie Lopez1, Kirill Nemirov1, Fanny Moncoq1, Amandine Noirat1, Benjamin Vesin1, Fabien Nevo1, Catherine Blanc1, Philippe Souque2, Houda Tabbal3, Emeline Simon3,4, Marine Le Dudal5, Françoise Guinet6, Laurence Fiette5, Hugo Mouquet7, François Anna1, Annette Martin3, Nicolas Escriou8, Laleh Majlessi1,$,#,* and Pierre Charneau1,2,$*
1 Institut Pasteur-TheraVectys Joint Lab, 28 rue du Dr. Roux, Paris F-75015, France
2 Molecular Virology and Vaccinology Unit, Institut Pasteur
3 Molecular Genetics of RNA Viruses Unit, Institut Pasteur. CNRS UMR3569, Université Paris 12 Diderot-Sorbonne, Paris Cité, Paris, France
4 Laboratory of Humoral Immunology, Institut Pasteur, INSERM U1222
5 Innovation Lab, Vaccines, Institut Pasteur
* Equal contribution of the authors
£ Co-senior and co-corresponding authors