Safety and immunogenicity of a heterologous booster with an RBD virus-like particle vaccine following two- or three-dose inactivated COVID-19 vaccine

Figures & data

Figure 1. Design principle of LYB001.

RBD, receptor binding domain; VLP, virus-like particle.

Figure 2. Study profile.

*One participant withdrew prior to booster vaccination due to prior receipt of a two-dose recombinant protein subunit vaccine against COVID-19 (ZF2001) other than ICV. ^†One participant was absent for blood collection at 90 days after the CoronaVac booster following two-dose ICV due to quarantine for COVID-19. ^‡One participant was absent for blood collection at 90 days after the CoronaVac booster following two-dose ICV due to quarantine for COVID-19. ^§One participant was absent for blood collection at 14 days after the 30 μg LYB001 booster following three-dose ICV due to quarantine for COVID-19. ICV, inactivated COVID-19 vaccine; SS, safety set; I-FAS, full analysis set for immunogenicity; I-PPS, per protocol set for immunogenicity (I-PPS1: I-PPS of 14 days after the booster; PPS2: I-PPS of 28 days after the booster), IPS, immunogenicity persistence set (IPS1: IPS of 90 days after the booster).

Table 1. Baseline characteristics of the participants.

	Booster after two-dose primary series of ICV		Booster after three-doses of ICV
	30 μg LYB001 (N = 30)	60 μg LYB001 (N = 30)	CoronaVac (N = 29)	30 μg LYB001 (N = 30)
Age (years)
Mean (SD)	29.4 (8.2)	29.6 (7.8)	30.1 (9.1)	30.3 (9.4)
Median (Range)	29.0 (18, 49)	27.5 (18, 54)	27.0 (19, 54)	27.0 (19, 52)
Sex
Male, n (%)	17 (56.67)	20 (66.67)	19 (65.52)	18 (60.0)
Female, n (%)	13 (43.33)	10 (33.33)	10 (34.48)	12 (40.0)
Ethnicity
Han Chinese, n (%)	29 (96.67)	30 (100.00)	27 (93.10)	26 (86.7)
Others, n (%)	1 (3.33)	0 (0.00)	2 (6.90)	4 (13.3)
History of prior infection (self-reported), n (%)	30 (100.0)	30 (100.0)	29 (100.0)	30 (100.0)
Prime-boost intervals
Mean (SD)	267.8 (31.9)	276.9 (25.0)	290.2 (37.0)	216.4 (37.3)
Median (Range)	264.0 (195, 330)	274.0 (231, 338)	288.0 (232, 362)	202.5 (183, 373)
Pre-booster immunity
GMCs of spike protein binding IgGs (95% CI), mIU/mL	17.3 (13.1, 22.9)	14.6 (11.8, 18.1)	17.2 (12.4, 24.0)	164.1 (113.3, 237.6)
GMTs of pseudovirus neutralizing antibody against prototype (95% CI)	8.5 (6.3, 11.6)	7.0 (5.2, 9.2)	9.0 (6.3, 12.7)	83.9 (55.5, 126.8)
GMTs of pseudovirus neutralizing antibody against BA.4/5 (95% CI)	5.0 (5.0, 5.0)	5.0 (5.0, 5.0)	5.0 (5.0, 5.0)	9.4 (6.2, 14.0)

SD, standard deviation; GMC, geometric mean concentration; GMT, geometric mean titer.

Table 2. Overall adverse events or reactions after booster administration.

Participants with at least one		Booster after two-dose primary series of ICV			Booster after three-dose ICV
		30 μg LYB001 (N = 30) n (%)	60 μg LYB001 (N = 30) n (%)	CoronaVac (N = 29) n (%)	30 μg LYB001 (N = 30) n (%)
Primary endpoints
AEs		24 (80.0)	22 (73.3)	10 (34.5)	20 (66.7)
Adverse reactions		23 (76.7)	20 (66.7)	9 (31.0)	19 (63.3)
Grade 3 or worse AEs		0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
Grade 3 or worse adverse reactions		0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Solicited local adverse reactions	overall	21 (70.0)	17 (56.7)	5 (17.2)	18 (60.0)
	mild	20 (66.7)	17 (56.7)	5 (17.2)	18 (60)
	moderate	1 (3.3)	0 (0.0)	0 (0.0)	0 (0.0)
	severe	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Pain	incidence	21 (70.0)	17 (56.7)	5 (17.2)	18 (60.0)
	median duration	2.0	2.0	2.0	2.0
Swelling	incidence	2 (6.7)	1 (3.3)	0 (0.0)	0 (0.0)
	median duration	2.0	2.0	2.0	2.0
Redness	incidence	1 (3.3)	0 (0.0)	0 (0.0)	0 (0.0)
	median duration	2.5	1.0	/	/
Pruritus	incidence	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
	median duration	/	1.0	/	/
Solicited systemic adverse reactions	overall	6 (20.0)	5 (16.7)	1 (3.4)	2 (6.7)
	mild	6 (20.0)	5 (16.7)	1 (3.4)	2 (6.7)
	moderate	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
	severe	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Fatigue	incidence	5 (16.7)	3 (10.0)	1 (3.4)	2 (6.7)
	median duration	1.0	1.0	1.0	3.0
Nausea	incidence	1 (3.3)	0 (0.0)	0 (0.0)	0 (0.0)
	median duration	1.0	/	/	/
Myalgia	incidence	0 (0.0)	2 (6.7)	0 (0.0)	0 (0.0)
	median duration	/	1.5	/	/
Headache	incidence	2 (6.7)	0 (0.0)	0 (0.0)	1 (3.3)
	median duration	1.0	/	/	1.0
Cough	incidence	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
	median duration	/	4.0	/	/
Diarrhea	incidence	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
	median duration	/	1.0	/	/
Acute allergic reaction (rash)	incidence	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
	median duration	/	5.0	/	/
Unsolicited adverse reactions		7 (23.3)	5 (16.7)	4 (13.8)	8 (26.7)
Secondary endpoints
SAE		0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
AESI		0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
AEs leading to withdrawal		0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Clinically significant safety laboratory measures
Hematology	White blood cell count increased	2 (6.7)	0 (0.0)	0 (0.0)	0 (0.0)
	Lymphocyte count increased	1 (3.3)	0 (0.0)	0 (0.0)	0 (0.0)
Blood chemistry	Alanine aminotransferase increased	2 (6.7)	0 (0.0)	0 (0.0)	0 (0.0)
	Blood urea increased	2 (6.7)	0 (0.0)	0 (0.0)	1 (3.3)
	Blood glucose increased	1 (3.3)	0 (0.0)	0 (0.0)	1 (3.3)
	Blood creatinine increased	1 (3.3)	1 (3.3)	1 (3.4)	0 (0.0)
Coagulation function		0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Urinalysis	Red blood cells urine positive	1 (3.3)	0 (0.0)	0 (0.0)	3 (10.0)*

The incidence of adverse events or reactions is presented as n (%). *Two participants reported positive urine red blood cells at baseline without clinical significance. AEs, adverse events; ICV, inactivated COVID-19 vaccine; SAE, serious adverse event; AESI, adverse event of special interest.

Figure 3. VSV-based neutralizing antibody titers against prototype SARS-CoV-2 and Omicron BA.4/5 strain.

Antibody values less than the lower limit of detection (LOD = 10) were replaced by 0.5 × LOD. The individual data in the I-I-30 L, I-I-60 L, I-I-C, and I-I-I-30 L groups are indicated by Δ, ▽, ○, ▲, respectively. VSV, vesicular stomatitis virus; I-I-30 L, 30 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-60 L, 60 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-C, CoronaVac booster after two-dose inactivated COVID-19 vaccine; I-I-I-30 L, 30 μg LYB001 booster after three-dose inactivated COVID-19 vaccine.

Figure 4. The spike protein binding IgGs at baseline and 14, 28, and 90 days after booster administration.

Antibody values less than the lower limit of detection (LOD = 20) were replaced by 0.5 × LOD. The data in the I-I-30 L, I-I-60 L, I-I-C, and I-I-I-30 L groups are indicated by Δ, ▽, ○, ▲, respectively. I-I-30 L, 30 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-60 L, 60 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-C, CoronaVac booster after two-dose inactivated COVID-19 vaccine; I-I-I-30 L, 30 μg LYB001 booster after three-dose inactivated COVID-19 vaccine.

Figure 5. RBD-specific IFN-γ, IL-2, or IL-4 secreting T-cells measured by ELISpot assay.

Bars and numbers in the figure indicate group medians, and error bars indicate interquartile range. The individual data in the I-I-30 L, I-I-60 L, I-I-C, and I-I-I-30 L groups are indicated by Δ, ▽, ○, ▲, respectively. RBD, receptor binding domain; I-I-30 L, 30 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-60 L, 60 μg LYB001 booster after two-dose inactivated COVID-19 vaccine; I-I-C, CoronaVac booster after two-dose inactivated COVID-19 vaccine; I-I-I-30 L, 30 μg LYB001 booster after three-dose inactivated COVID-19 vaccine.

Data availability statement

The data used in this study are available from the corresponding author upon reasonable request.