Table 2.

Overview of published preclinical studies that combined the nucleocapsid and spike protein of SARS-CoV-2.

	Platform	Animal model	Antigen	Dose and route	Immune response	Protection	Cross-reaction with VOC	Ref
1	Protein, P.S.	BALB/c	S1 + N S2 + N	Two, 25 µg S1/S2 + 25 µg N, IP	IgG and IgG2 Ab IFN-γ	UD	UD	[80]
2	Protein, P.S.	BALB/c and C57BL/6 and K18-h ACE-II mice Rats Cambodian macaques	RBD fused tetanus toxoid epitope P2 (RBD-P2) + nucleocapsid	Two, IM 30 µg and 50 µg RBD-P2 3 µg and 3 µg of N	IgG1 and IgG2 Ab IFN-γ and IL-4 CD69+, CD62L, and CD44+	Positive	UD	[81]
3	Protein, P.S.	BALB/c mice	RBD + N	15 µg RBD + 15 µg N. SB	IgG1 and IgG2a Ab IFN- γ, granzyme B, IL-4, and IL-12	UD	UD	[82]
	Protein, P.S.	C57BL/6 and K18-h ACE-II mice	N + SFLmut	8 µg NC + 8 µg SFLmut IN	IgG and IgA Ab IFN-γ and IL-4 Tissue-resident memory cells	Positive	B.1351 and B.1.617.2	[83]
4	Protein, E.S.	BALB/c mice	S1 + N RBD + N	Three, 10 µg S1/RBD + 10 µg N, IP	IgM, IgG1, and IgG2a Ab IFN-γ, TNF-α, and IL-2	UD	Alpha and Beta	[84]
5	Protein, E.S	BALB/c mice	N + RBD	Three, 50 µg SC or IN	IgG1, IgG2a, and IgA Ab	UD	Delta	[85]
6	Protein, E.S	C57BL/6 mice	S1 + N	Two, S1 + N 0.1/1 µg IN	IgG, IgA, and Ab IFN-γ and IL-5	UD	UD	[86]
7	Protein, E.S.	K18-h ACE-II mice and BALB/c mice	S1 + S2 + N	Two S1 + S2 10 µg N 2.5 µg IP	IgG Ab IFN-γ	Positive	UD	[87]
8	Protein E.S. and E.S	BALB/c mice	RBD + N	Two, 10 µg RBD + 10 µg N IM	IgG Ab IFN-γ	UD	D614G and Delta	[88]
9	Protein, E.S.	BALB/c mice	S1 + N RBD + N	Three, S1 + N or RBD + N 40, 80, or 120 µg	IgG Ab IFN-γ, IL-4, and IL-12	UD	UD	[89]
10	Protein, E.S.	BALB/c mice Rabbits	Exosome decorated with S + exosome decorated with N	One 25 ng S + 5 ng NC, 125 ng S + 10 ng N IM	IgG Ab IFN-γ	UD	Delta and Omicron	[90]
11	Protein, P.S.	K18-h ACE-II mice Syrian hamster	Fusion protein S and N (SpiN)	Two, 10 µg SpiN, IM	IgG Ab IFN-γ CD44+, CD69+, and CD62L+	Positive	Omicron	[91]
12	Protein, P.S.	K18-h ACE-II mice	Chimeric protein Spike and N fused to BCG (rBCG-ChD6)	Two, 106 CFU rBCG-chD6. SC	IgG1 and IgG2c Ab IFN-γ and IL-6	Positive	Gamma	[92]
13	Protein, E.S.	BALB/c mice	Fusion protein nucleocapsid RBD	Booster N-RBD, 18 µg. IN	IgG Ab	UD	D614G, Delta, and Omicron	[93]
14	Viral vector Ad5	K18-h ACE-II mice	Spike + nucleocapsid	One, 109 PFU Ad5-N + S	IgG Ab IFN-γ	Positive	UD	[94]
15	Viral vector Ad5	CD-1 mice	Spike-fusion + nucleocapsid fused to ETSD	Two, 109 VP. SC and IN	IgG1. IgG2a, and IgG2b IFN-γ	UD	UD	[95]
16	Viral vector Ad5	Rhesus macaques	Spike-fusion + nucleocapsid fused to ETSD	Three, 1011 VP hAd5 S-fusion + N-ETSD. SC and O	IgG Ab IFN-γ	Positive	UD	[96]
17	Viral vector MVA	Rhesus macaques	Spike stabilize (SdFCS) + nucleocapsid	Two, 108 PFU MVA-N/SdFCS-N, BU, IM, and SL	IgG Ab IFN-γ	Positive	Delta	[97]
18	Viral vector MVA	BALB/c and C57BL/6 Mice	Spike + nucleocapsid	Two, 107 PFU. MVA-N/S, and IP	IgG Ab IFN-γ, TNF-α, and IL-4	UD	UD	[98]
19	Viral vector MVA	Syrian hamster and rhesus macaques	Spike + nucleocapsid	Two, 1 × 108 PFU or 2.5 × 108 MVA-N/S, IM or IN	IgG Ab IFN-γ, IL-2, IL-4	Positive	Alpha, Beta, Gamma, and Delta	[99]
20	Viral vector MVA	BALB/c mice	Spike + nucleocapsid	Two, 1 × 107 PFU or 2.5 × 108 MVA-N/S, IM, or IN	IgG and IgA Ab IFN-γ and granzyme B CCL2, CXCL10, CCL3, TNF-α, and IL-6	Positive	UD	[100]
21	Viral vector MVA	Syrian hamster	Spike + nucleocapsid	Two, 1 × 108 PFU or 2.5 × 108 sMVA-N/S, IM	IgG Ab	Positive	Beta and Omicron	[101]
22	Viral vector MVA	K18-h ACE-II mice	Spike + nucleocapsid	One, 1 × 108 PFU MVA-ST/N, IM	IgG Ab IFN-γ	Positive	UD	[102]
23	Viral vector VACV	Syrian hamster	Spike + nucleocapsid	One, 2 × 107 PFU VACV N + S (rACAM2000SN) IM	IgG Ab	Positive	UD	[103]
24	Viral vector VSV	Syrian hamster	Spike + nucleocapsid	One, 1 × 105 PFU VSV-SARS2-N+S IM or IN	IgG Ab	Positive	Alpha, Beta, and Delta	[104]
25	DNA	BALB/c mice Cynomolgus monkey	S-RBD + nucleocapsid (GX-19 N)	Two, 12 µg GX-19 N, IM Two, 3 mg GX-19 N, IM	IgG Ab IFN-γ	UD	UD	[105]
26	RNA SaRNA	Swiss mice Syrian hamster	RBD + nucleocapsid	Two, 0.5 µg S-RBD saRNA + 0.5 µg N saRNA (ZIP1642) IM	IgG Ab IFN-γ, TNF-α, IL-2, and IL-4	Positive	Beta and Delta	[106]
27	RNA MRNA	BALB/c mice Syrian hamster	Spike + nucleocapsid	Two, 1 µg mRNA-S + 1 µg mRNA-N IM Two, 2 µg mRNA-S + 2 µg mRNA-N IM	IgG Ab IFN-γ, TNF-α, and IL-2	Positive	Delta and Omicron	[107]

IP, intraperitoneal; IM, intramuscular; IT, intratracheal; SC, subcutaneous; IV, intravenous; SL, sublingual; BU, buccal; LN, lymph node; UD, undetermined; procaryotic system; ES, eukaryotic system.