key: cord-0835039-8njrere6
authors: Abdoli, Asghar; Khanali, Javad; Azangou-Khyavy, Mohammadreza; Abbasi-Kangevari, Mohsen; Ghamari, Seyyed-Hadi; Malekpour, Mohammad-Reza; Jamshidi, Hamidreza; Taqavian, Mohammad; Baghal, Mehdi Lari; Jalili, Hasan
title: Omicron-Based Vaccine Candidate Elicits Potent Neutralizing Antibodies in the Animal Model
date: 2022-02-15
journal: bioRxiv
DOI: 10.1101/2022.02.11.480131
sha: 81bb5812bbe142fff07e5f5b2997c0df078955d1
doc_id: 835039
cord_uid: 8njrere6

The B.1.1.529 (Omicron) variant of SARS-CoV-2 with multiple novel mutations has reduced the neutralization potential of vaccinated individuals’ sera. World Health Organization has suggested that a vaccination strategy based on repeated booster doses is unlikely to be sustainable. The objective of this commentary was to investigate the safety and neutralizing antibody induction of the Omicron-based SARS-CoV-2 vaccine candidate, BIV1-CovIran Plus, against the Omicron variant on mice and guinea pig models. After isolation and characterization, the Omicron variant underwent chemical inactivation, purification, and was then formulated with alum adjuvant. A full human dose of BIV1-CovIran Plus was injected intraperitoneally to five female mice and two Guinea pigs for abnormal toxicity reactions evaluation and pathologic investigations. For potency evaluation, four groups of ten mice received two doses of BIV1-CovIran Plus or phosphate-buffered-saline at 7-day and 14-day intervals. The conventional virus-neutralizing test was conducted on sera acquired from vaccinated mice groups seven days after the second injection. There was no evidence of abnormal clinical symptoms macroscopic or microscopic tissue alterations among the animal models. In all samples from the study group that received two doses of BIV1-CovIran Plus at a 7-day interval, the sera at ≥1/32 times dilution would neutralize the Omicron variant SARS-CoV-2. Similarly, the sera of all samples from the study group, which received two doses of BIV1-CovIran Plus at a 14-day interval, at ≥1/64 times dilution, would neutralize the Omicron variant SARS-CoV-2. Moreover, six out of ten (60%) of the samples in this group would neutralize the Omicron variant of SARS-CoV-2 at 1/128 times dilution. CPE formation was observed in all samples from the control group, and no neutralizing activity was detected at any sera dilutions. BIV1-CovIran Plus was well-tolerated in the animal models, and no safety concerns were raised. Moreover, the vaccine candidate elicited protective neutralization against the Omicron variant. Future reports will focus on the use of the updated vaccine as a booster dose and the potency of the vaccine candidate on other SARS-CoV-2 variants.

The B.1.1.529 (Omicron) variant of SARS-CoV-2 was identified in South Africa in early November 2021 as a variant of concern (VOC), which rapidly became the dominant variant in many countries (1, 2) . With its high transmissibility and multiple novel spike (S) protein mutations, Omicron could escape from naturally acquired immunity while also challenging the effectiveness of current COVID-19 vaccines (2, 3) . The secondary attack rate for Omicron in fully-vaccinated and boostervaccinated individuals is shown to be approximately 2-4 times higher than the Delta variant, demonstrating strong evidence for immune evasion (4) . Emerging evidence from in-vitro studies suggests reduced neutralization potential of vaccinated individuals' sera against Omicron (1, 2, 5, 6) .

The health impacts of future SARS-CoV-2 transmission depend on evolving mitigation strategies by health systems and societies. World Health Organization has reportedly declared that vaccination strategy based on repeated booster doses is unlikely to be sustainable. In this sense, the current COVID-19 vaccines originally developed against ancestral strains may need to be updated (7) . Furthermore, in case of the future dominance of the Omicron variant and others originating from this variant, the development of updated vaccines would be crucial (8) . Thus, Omicron-based vaccines are being developed, and clinical trials have begun in late January 2022 (9,10).

SARS-CoV-2. In preclinical studies, the vaccine was safe and showed potency in inducing both humoral and cellular immunity (11) . In phase III clinical trial, which is currently under peer-review, a two-dose vaccine regimen was well tolerated, with no safety concerns, and conferred 70.5% and 83.1% efficacy against hospitalization and 5 ICU admission, respectively. The vaccine has reduced hospitalization by 86.4% and deaths by 98.3% (12) . After passing the sterility test, vaccine master seed and working seed were prepared.

The study was carried out among female, six-to-eight-week-old BALB/c mice and Guinea pig animal models provided by the Laboratory Animal Science Department, Pasteur Institute of Iran, Karaj, Iran. A full human dose (0.5 mL) of the BIV1-CovIran Plus was injected intraperitoneally to five female mice and two Guinea pigs for abnormal toxicity reactions evaluation. The animals 6 were observed for seven days for any evidence of ill-health. After seven days, a veterinary pathologist evaluated organs and tissues for any signs of adverse reactions (13) .

For potency evaluation, four groups of ten mice received two doses of BIV1-CovIran Plus or placebo (phosphate-buffered saline) at 7-day and 14-day intervals. The conventional virusneutralizing test (cVNT) was conducted on sera acquired from vaccinated mice groups seven days [ Figure 1 ]

There was no evidence of abnormal clinical symptoms, altered water or food intake, weight loss, and macroscopic tissue alterations among the mice and Guinea pigs that received BIV1-CovIran Plus. Moreover, there were no microscopic changes in the animals' liver, kidney, heart, and lung samples. 7 The neutralization potency of two doses of BIV1-CovIran Plus was assessed against the Omicron variant. In all samples from the study group that received two doses of BIV1-CovIran Plus at a 7day interval, the sera at ≥1/32 times dilution would neutralize the Omicron variant SARS-CoV-2.

Similarly, the sera of all samples from the study group, which received two doses of BIV1-CovIran Plus at a 14-day interval, at ≥1/64 times dilution, would neutralize the Omicron variant SARS-CoV-2. Moreover, six out of ten (60%) of the samples in this group would neutralize the Omicron variant of SARS-CoV-2 at 1/128 times dilution. CPE formation was observed in all samples from the control group, and no neutralizing activity was detected at any sera dilutions ( Figure 2 ).

[ Figure 2 ] BIV1-CovIran Plus was well-tolerated in the animal models, and no safety concerns were raised. Moreover, the vaccine candidate elicited protective neutralization against the Omicron variant in 100% of mice studied a week after the second injection.

The isolated virus used in the study was genetically identical to the B.1.1.529 variant, initially identified in South Africa (17) . Since the identification of Omicron in November 2021, vaccine manufacturers have begun developing variant-based vaccine candidates (9, 10) . While the initial Omicron peaks could plummet before these vaccines are commercially available (18) , this variant seems to have the potential to become a persistent variant that healthcare systems need to deal with. Moreover, other SARS-CoV-2 variants could emerge and further challenge the effectiveness of current vaccines (18) . Thus, developing variant-specific COVID-19 vaccine candidates as boosters could be potential mitigation strategies (19). The process of virus inactivation, validation, purification, and formulation was done in a month-length timeline, indicating the early response capacity to potential new circulating variants of concern.

8 In this sense, it remains unclear whether the immunologically naïve populations should be offered the vaccines originally manufactured against the Wuhan variant or the variant-based vaccine candidates (20) .

Even though the promising preliminary results of the use of BIV1-CovIran Plus vaccine candidate against the Omicron variant is presented here, using the updated vaccine as a booster dose for BIV1-CovIran as well as the potency of the vaccine candidate on other SARS-CoV-2 variants have been investigated and will be reported in the upcoming publications. 

Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa

Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants. medRxiv

Accelerated COVID-19 vaccine development: milestones, lessons, and prospects

SARS-CoV-2 Omicron VOC Transmission in Danish Households. medRxiv

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant

Reduced Neutralization of SARS-CoV-2 Omicron Variant by Vaccine Sera and Monoclonal Antibodies. medRxiv

WHO. Interim Statement on COVID-19 vaccines in the context of the circulation of the 11

CoV-2 Variant from the WHO Technical Advisory Group on COVID-19

Vaccine Composition (TAG-CO-VAC)

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron

Announces First Participant Dosed in Phase 2 Study of Omicron-Specific Booster Candidate and Publication of Data on Booster Durability Against Omicron Variant

Pfizer and BioNTech Initiate Study to Evaluate Omicron-Based COVID-19 Vaccine in Adults 18 to 55 Years of Age | Pfizer

Safety and potency of BIV1-CovIran inactivated vaccine candidate for SARS-CoV-2: A preclinical study

Effectiveness of COVID-19 Vaccines in preventing Infectiousness, Hospitalization and Mortality: A Historical Cohort Study Using Iranian Registration Data During Vaccination program

Study designs for the nonclinical safety testing of new vaccine products

Homologous or heterologous booster of inactivated vaccine reduces SARS-CoV-2 Omicron variant escape from neutralizing antibodies. Emerg Microbes Infect

Safety and potency of BIV1-CovIran inactivated vaccine candidate for SARS-CoV-2: A preclinical study

Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell [Internet

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

Does the world need an Omicron vaccine? What researchers say

Fauci: Omicron-specific vaccines "prudent" but may be unnecessary | TheHill

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron