New nanoparticle-based COVID vaccines induce long-term neutralizing antibody response

The global coronavirus disease 2019 (COVID-19) pandemic has affected almost every country in the world as more than 6.1 million deaths have been reported due to COVID-19. The development and mass administration of vaccines has enabled many developed countries to begin to recover from the current pandemic; however, developing countries have not yet received enough vaccine doses to boost the immunity of their own citizens.

Newly emerging causative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants also continue to show the ability to evade both vaccine-induced and natural immunity, highlighting the need for further research on vaccines and immunity. In a recent study published on the preprint server bioRxiv*, researchers report the results of a new SARS-CoV-2 vaccine currently in a phase III clinical trial called I53-50.

Study: Durable protection against SARS-CoV-2 Omicron induced by an adjuvanted subunit vaccine. Image Credit: solarseven / Shutterstock.com

About the study

Four groups of male rhesus macaques were used for the present study. In the first group, five macaques received immunization against RBD-Wu-AS03 on days 0 and 21, followed by a booster dose about six months later.

The second group received two doses of RBD-I53-50-Wu, and the third group received two doses of HexaPro-I53-50. RBD-I53-50-Wu and HexaPro-I53-50 were administered on days 0 and 21, along with AS03 adjuvant. These mice were then boosted with an I53-50 nanoparticle displaying RBD-Beta stabilized with Rpk9 mutations.

The last group consisted of unvaccinated controls. All animals were challenged with 2×106 units of the SARS-CoV-2 Omicron variant. The first group was tested six weeks after the final dose, while the other two groups were tested about six months after the last booster.

Study results

Vaccination with RBD-Wu-AS03 succeeded in obtaining binding IgG titers against the spike protein of SARS-CoV-2 wild-type, Omicron and Beta strains at day 21. These titers increased tenfold after the second immunization but were reduced to six-month pre-booster levels.

The booster dose further enhanced the humoral immune response, as evidenced by a 2.5-fold and four-fold increase in titers against the wild-type and Omicron variants, respectively. Neutralizing antibody (nAb) responses were detected against the ancestral strain after the first dose, which increased approximately 20-fold after the second dose.

T cell responses induced by RBD-nanoparticle vaccination with AS03 adjuvant.  a–b, Frequency of Spike-specific CD4 T cell responses against ancestral (left panel) and Omicron (right panel) strains in the RBD-Wu/RBD-Wu/RBD-Wu group.  c–d, Frequency of Spike-specific CD4 T cell responses against ancestral (left panel) and Omicron (right panel) strains in RBD-Wu/RBD-Wu/RBD-β (blue) and HexaPro/HexaPro /RBD-β groups (red).  CD4 T cells secreting IL-2, IFN-γ or TNF are shown as Th1 type responses (a,c) and IL-4 producing CD4 T cells are shown as responses Th2-type (b,d) Statistical differences between time points were determined using Wilcoxon's matched pairs signed rank test.  e, Pie charts representing the proportions of RBD-specific CD4 T cells expressing one, two, or three cytokines, as indicated in the legend.  f, Comparison of CD4 T cell frequencies between ancestral and Omicron viral strains measured at day 7 after final booster immunization.  Statistical difference was determined using Wilcoxon's matched pairs signed rank test.  The % value above Omicron represents the proportion of responses specific to Omicron versus responses against the ancestral strain.  g, Spike-specific IL-21+, CD154+ and CD154+ IL-21+ CD4 T cell responses measured in blood on day 7 after final booster immunization.  In all plots, each circle represents an animal, In f and g, black, blue and red colors indicate RBD-Wu/RBD-Wu/RBD-Wu, RBD-Wu/RBD-Wu/RBD-β and HexaPro/ HexaPro/RBD-β groups, respectively.

T cell responses induced by RBD-nanoparticle vaccination with AS03 adjuvant. a–b, Frequency of Spike-specific CD4 T cell responses against ancestral (left panel) and Omicron (right panel) strains in the RBD-Wu/RBD-Wu/RBD-Wu group. c–d, Frequency of Spike-specific CD4 T cell responses against ancestral (left panel) and Omicron (right panel) strains in RBD-Wu/RBD-Wu/RBD-β (blue) and HexaPro/HexaPro /RBD-β groups (red). CD4 T cells secreting IL-2, IFN-γ or TNF are shown as Th1 type responses (a,c) and IL-4 producing CD4 T cells are shown as responses Th2-type (b,d) Statistical differences between time points were determined using Wilcoxon’s matched pairs signed rank test. e, Pie charts representing the proportions of RBD-specific CD4 T cells expressing one, two, or three cytokines, as indicated in the legend. f, Comparison of CD4 T cell frequencies between ancestral and Omicron viral strains measured at day 7 after final booster immunization. Statistical difference was determined using Wilcoxon’s matched pairs signed rank test. The % value above Omicron represents the proportion of responses specific to Omicron versus responses against the ancestral strain. g, Spike-specific IL-21+, CD154+ and CD154+ IL-21+ CD4 T cell responses measured in blood on day 7 after final booster immunization. In all plots, each circle represents an animal, In f and g, black, blue and red colors indicate RBD-Wu/RBD-Wu/RBD-Wu, RBD-Wu/RBD-Wu/RBD-β and HexaPro/ HexaPro/RBD-β groups, respectively.

Notably, this immune response was not observed against the Omicron strain, as only a weak nAb response was detected. After the booster dose, the response against Omicron and the ancestral strain increased significantly.

In groups two and three, the booster dose of RBD-Beta elicited IgG responses similar to those seen in group one. This was a significant improvement, considering the typical reduction in immune response over time. Neutralizing activity was also still detectable before the boost and then increased to significant levels after the final immunization.

As many previous studies have observed, antibody titers were significantly lower against the Omicron variant compared to the ancestral SARS-CoV-2 strain. Using a power-law decay model assuming that decay rates decrease over time, the estimated half-life of binding IgG antibodies was found to be very similar between the different groups.

T-cell responses were measured using intracellular cytokine staining assays after stimulation of peripheral blood mononuclear cells (PBMCs) with peptide pools spanning spike proteins of different variants. RBD-Wu-AS03 vaccination elicited Th1 and Th2 CD4+ T cell responses, which fell to baseline levels six months before the booster dose increased them again.

Similar responses were observed in groups two and three. These responses had decreased significantly five months after the booster, but remained detectable.

Spike-specific B cells were assessed using flow cytometry analysis of PBMCs with fluorescently labeled spike protein of the different variants. To this end, a robust response was observed 21 days after the second vaccination with RBD-Wu-AS03. The third dose increased the frequency of tip-specific B cells approximately tenfold; however, the frequency gradually decreased and reached pre-vaccination levels by six months.

conclusion

The new vaccine described in the present study provides effective protection against SARS-CoV-2, as it induced high levels of humoral and cellular immune responses. In addition, this vaccine was found to confer protection against the Omicron variant six weeks after the last booster. The current results also demonstrate the durability of the induced immune response, especially with regard to neutralizing antibody titers.

As concerns continue to be raised about the rapid decline in immunity provided by currently approved COVID-19 vaccines, the vaccine described here may be more effective in providing long-term immunity against COVID-19.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information

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