# Analysis of Host Immunological Response of Adenovirus-Based COVID-19 Vaccines

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## Abstract

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## 1. Introduction

## 2. Model

#### 2.1. Parameter Fitting

#### 2.2. Sensitivity Analysis

## 3. Results

#### 3.1. Sensitivity Analysis

#### 3.2. Mechanism of Vaccine-Induced Immunity with Booster Delay and Sparing

#### 3.2.1. Antibody and Cytotoxic T-Cell Responses

#### 3.2.2. Cytokines, B and Th${}_{0}$ Cell Responses

#### 3.2.3. Protective Capacity

## 4. Discussion

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

## Abbreviations

APC | Antigen-Presenting Cell |

MHC | Major Histocompatibility Complex |

$T{h}_{0}$ | T Helper Cell Type 0 |

$T{h}_{1}$ | T Helper Cell Type 1 |

$T{h}_{2}$ | T Helper Cell Type 2 |

NK | Natural Killer Cell |

CTL | Cytotoxic T Lymphocyte |

IL | Interleukin |

$IFN$ | Interferon |

$TGF$ | Transforming Growth Factor |

$NAb$ | Neutralizing Antibody |

$IgG$ | Immunoglobulin G |

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**Figure 1.**Vaccine-induced immune activation pathway for an adenovirus vaccine. Faint background: The subsequent downstream of signaling pathways activated through adaptive immunity when SARS-CoV-2 enters the human cell. Highlighted compartments describe vector-based vaccine-induced immune system stimulation that is modeled explicitly in this study. The dashed arrows show implicit communications between cells and cytokines, and the only solid arrow indicates the production of antibodies by B-cells.

**Figure 2.**Antibody and IFN$\gamma $ fit to the clinical trial data [1]. Blue and red solid lines: predicted results for participants who received one (blue) or two doses (red), with a boost dose at day 28 (shown by black vertical dashed lines). Left: The purple horizontal dashed line shows the maximum stimulated antibody level post-boost.

**Figure 3.**Sensitivity analysis of Model (1) using 10,000 iterations of a Latin hypercube sampling (LHS) method with a partial rank correlation coefficient (PRCC). PRCC values with magnitude close to unity indicate that the parameter has a strong impact on the model output [38].

**Figure 4.**Antibody (IgG) and CTL outcomes with standard (SD) and low dose (LD), with and without delay. Model predictions of antibody, first row, and cytotoxic T-cells, second row, with second dose vaccination on days: 28 (week:4), 42 (week:6), 56 (week:8), 70 (week:10), 84 (week:12), 98 (week:14), 112 (week:16), 126 (week:18), and 140 (week:20, shown by colored vertical dashed lines.). The second dose value (sd) in panel (

**a**) is the same as the initial dose (id) value: (sd = Id = 1000 vaccine particles), in panel (

**b**) it is decreased by half (sd = Id/2 = 500 vaccine particles), and in panel (

**c**) is decreased by a quarter (sd = Id/4 = 250 particles).

**Figure 5.**Model predictions of IFN$\gamma $, IL-6, plasma B-cells and T helper type 0 cells Th${}_{0}$ for the received boost dose (1000 vaccine particles) on days 28 (blue curve), 42 (red curve), 56 (green curve) and 70 (purple curve). The vertical dashed lines show the second dose injection days.

Variable | Definition |
---|---|

V | Vaccine cell |

T | T helper type 0 cell (Th${}_{0}$) |

F | Interferon gamma ($IFN\gamma $) |

I | Interleukin 6 ($IL-6$) |

B | Plasma B-cell |

A | Antibody |

C | Cytotoxic T-cell |

Parameter | Definition | Value | Unit | Comment |
---|---|---|---|---|

${\alpha}_{16}$ | Vaccine neutralizing rate by antibody molecules | 1 $\times \phantom{\rule{3.33333pt}{0ex}}{10}^{-6}$ | day${}^{-1}$(a.u.)${}^{-1}$ | Handle et al., 2018 |

${\gamma}_{v}$ | Vaccine clearance rate | 0.2 | day${}^{-1}$ | Cao et al., 2016 |

${\mu}_{21}$ | Th${}_{0}$ cells activation rate by vaccine particles | 0.035 | day${}^{-1}$ | Chosen |

${\gamma}_{t}$ | Th${}_{0}$ cells natural death rate | 0.055 | day${}^{-1}$ | Cao et al., 2016 |

${\mu}_{32}$ | IFN$\gamma $ stimulation rate by Th${}_{0}$ | 2.55 | day${}^{-1}$ | Fitted |

${\gamma}_{f}$ | IFN$\gamma $ natural degradation rate | 0.13 | day${}^{-1}$ | Fitted |

${\alpha}_{37}$ | IFN$\gamma $ absorption rate by CTL for mitotic signals | 0.006 | day${}^{-1}$(a.u.)${}^{-1}$ | Fitted |

${\mu}_{42}$ | IL6 release rate by Th${}_{0}$ | 1.3 | day${}^{-1}$ | Fitted |

${\gamma}_{i}$ | IL6 natural degradation rate | 0.0008 | day${}^{-1}$ | Chosen |

${\alpha}_{45}$ | IL6 absorption rate by B-cells for mitotic signals | 0.0001 | day${}^{-1}$(a.u.)${}^{-1}$ | Fitted |

${\mu}_{52}$ | B-cell activation rate by Th${}_{0}$ | 0.02 | day${}^{-1}$ | Fitted |

${\alpha}_{54}$ | B-cell stimulation rate by IL | 0.05 | day${}^{-1}$(a.u.)${}^{-1}$ | Fitted |

${S}_{i}$ | B-cell duplication threshold due to IL | 1000 | a.u. | Chosen |

${\gamma}_{b}$ | B-cell natural death rate | 0.06 | day${}^{-1}$ | Fitted |

$\epsilon {\mu}_{65}$ | Released Ab rate by B-cells | 7 | day${}^{-1}$ | Fitted |

${\gamma}_{a}$ | Ab natural degradation rate | 0.06 | day${}^{-1}$ | Fitted |

${\alpha}_{61}$ | Ab - V cells binding rate | 1 $\times \phantom{\rule{3.33333pt}{0ex}}{10}^{-7}$ | day${}^{-1}$(a.u.)${}^{-1}$ | Chosen |

${\mu}_{71}$ | CTL activation rate by vaccine | 0.002 | day${}^{-1}$ | Fitted |

${\alpha}_{73}$ | CTL stimulation rate by IFN$\gamma $ | 0.09 | day${}^{-1}$(a.u.)${}^{-1}$ | Fitted |

${S}_{f}$ | CTL duplication threshold due to IFN$\gamma $ | 600 | a.u. | Chosen |

${\gamma}_{c}$ | CTL natural death rate | 0.01 | day${}^{-1}$ | Wang et al., 2016 |

Variable | Parameter | Absolute PRCC Value |
---|---|---|

A (Antibody) | ${\gamma}_{b}$ | $0.8<PRCC<0.9$ |

${\mu}_{21}$ | ≈$0.8$ | |

${\gamma}_{v}$ | ≈$0.8$ | |

$\epsilon {\mu}_{65}$ | ≈$0.7$ | |

${\alpha}_{54}$ | $0.6<PRCC<0.7$ | |

${\gamma}_{t}$ | ≈$0.6$ | |

${\mu}_{52}$ | ≈$0.6$ | |

${\gamma}_{a}$ | $0.5\le PRCC<0.6$ | |

${\alpha}_{73}$ | $0.8<PRCC<0.9$ | |

${\gamma}_{v}$ | $0.8<PRCC<0.9$ | |

${\gamma}_{t}$ | ≈$0.7$ | |

C (CTL) | ${\mu}_{21}$ | $0.6<PRCC<0.7$ |

${\mu}_{32}$ | $0.6<PRCC<0.7$ | |

${S}_{f}$ | ≈$0.7$ | |

${\mu}_{71}$ | ≈$0.6$ | |

F (IFN$\gamma $) | ${\mu}_{21}$ | ≈$0.9$ |

${\mu}_{32}$ | ≈$0.9$ | |

${\gamma}_{v}$ | $0.7<PRCC<0.8$ | |

${\gamma}_{t}$ | ≈$0.6$ | |

${\mu}_{71}$ | ≈$0.5$ | |

${\alpha}_{37}$ | ≈$0.5$ | |

${\mu}_{21}$ | ≈1 | |

T (Th${}_{0}$) | ${\gamma}_{v}$ | ≈1 |

${\gamma}_{t}$ | ≈$0.7$ | |

Plasma B | ${\mu}_{21}$ | ≈$0.8$ |

${\gamma}_{b}$ | ≈$0.8$ | |

${\gamma}_{v}$ | $0.7<PRCC<0.8$ | |

${\mu}_{52}$ | ≈$0.7$ | |

${\alpha}_{54}$ | $0.6<PRCC<0.7$ | |

${\gamma}_{t}$ | ≈$0.6$ | |

I (IL6) | ${\mu}_{42}$ | ≈$0.9$ |

${\mu}_{21}$ | ≈$0.9$ | |

${\gamma}_{v}$ | $0.8<PRCC<0.9$ | |

${\gamma}_{t}$ | $0.8<PRCC<0.9$ |

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**MDPI and ACS Style**

Farhang-Sardroodi, S.; Korosec, C.S.; Gholami, S.; Craig, M.; Moyles, I.R.; Ghaemi, M.S.; Ooi, H.K.; Heffernan, J.M. Analysis of Host Immunological Response of Adenovirus-Based COVID-19 Vaccines. *Vaccines* **2021**, *9*, 861.
https://doi.org/10.3390/vaccines9080861

**AMA Style**

Farhang-Sardroodi S, Korosec CS, Gholami S, Craig M, Moyles IR, Ghaemi MS, Ooi HK, Heffernan JM. Analysis of Host Immunological Response of Adenovirus-Based COVID-19 Vaccines. *Vaccines*. 2021; 9(8):861.
https://doi.org/10.3390/vaccines9080861

**Chicago/Turabian Style**

Farhang-Sardroodi, Suzan, Chapin S. Korosec, Samaneh Gholami, Morgan Craig, Iain R. Moyles, Mohammad Sajjad Ghaemi, Hsu Kiang Ooi, and Jane M. Heffernan. 2021. "Analysis of Host Immunological Response of Adenovirus-Based COVID-19 Vaccines" *Vaccines* 9, no. 8: 861.
https://doi.org/10.3390/vaccines9080861