A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters.
A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters.
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DOI：
10.1073/pnas.2109744118
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发表时间：
2021-12-14
影响因子：
11.1
通讯作者：
Buchholz UJ
中科院分区：
文献类型：
--
作者：
Liu X;Luongo C;Matsuoka Y;Park HS;Santos C;Yang L;Moore IN;Afroz S;Johnson RF;Lafont BAP;Martens C;Best SM;Munster VJ;Hollý J;Yewdell JW;Le Nouën C;Munir S;Buchholz UJ
儿童SARS-CoV-2感染虽然通常是轻微的，但与大量发病率相关，并有助于传播动态。目前还没有针对幼儿的SARS-CoV-2疫苗。牛/人副流感病毒3 （B/HPIV3）载体用于儿童鼻内免疫先前在1/2期研究中进行了评估，并且在2个月大的儿童中具有良好的耐受性。本文描述了一种表达SARS-CoV-2 S蛋白（S- 2p）预灌注稳定版本的B/HPIV3载体，并表明单次鼻内剂量在仓鼠模型（目前最强大的SARS-CoV-2攻击模型）中具有高度免疫原性和对SARS-CoV-2攻击的保护性。基于这些结果，B/HPIV3/S-2P代表了一种有前景的疫苗候选物，可作为儿科鼻内免疫HPIV3和SARS-CoV-2的疫苗进行临床评估。所有年龄组都需要能够限制SARS-CoV-2在呼吸道复制的单剂量疫苗，以帮助控制COVID-19。我们基于复制型嵌合牛/人副流感病毒3型（B/HPIV3）开发了婴儿和儿童抗COVID-19的鼻内活载体疫苗，该疫苗表达SARS-CoV-2的主要保护性和中和性抗原-天然(S)或预灌注稳定（S- 2p） SARS-CoV-2刺突蛋白。B/HPIV3/S和B/HPIV3/S- 2p的体外复制效率与B/HPIV3一样高，且能稳定表达SARS-CoV-2。在仓鼠中，与B/HPIV3/S- 2p相比，单次鼻内剂量的B/HPIV3/S诱导血清SARS-CoV-2中和抗体（高12倍），血清SARS-CoV-2蛋白IgA和IgG（5倍和13倍），以及受体结合域IgG（10倍）的滴度显着提高。抗体对谱系A、B.1.1.7和B.1.351的SARS-CoV-2表现出广泛的中和活性。免疫4周后，用104.5 50%组织培养感染剂量（TCID50）的SARS-CoV-2经鼻攻击仓鼠。在B/HPIV3空载体免疫的仓鼠中，SARS-CoV-2复制到肺中的平均滴度为106.6 TCID50/g，鼻组织中的平均滴度为107 TCID50/g，并引起中度体重减轻。在B/HPIV3/ s免疫的仓鼠中，SARS-CoV-2攻击病毒在鼻组织中减少了20倍，在肺中检测不到。在B/HPIV3/ s - 2p免疫的仓鼠中，鼻组织和肺部未检出感染性攻毒病毒；B/HPIV3/S和B/HPIV3/S- 2p完全防止SARS-CoV-2攻击后体重下降。B/HPIV3/S-2P是一种很有希望保护婴幼儿免受HPIV3和SARS-CoV-2感染的候选疫苗。
Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. No SARS-CoV-2 vaccines are available for young children. Bovine/human parainfluenza virus 3 (B/HPIV3) vectors for intranasal immunization of children were evaluated previously in phase 1/2 studies and were well-tolerated in children as young as 2 mo of age. This manuscript describes a B/HPIV3 vector expressing a prefusion-stabilized version of the SARS-CoV-2 S protein (S-2P), and shows that a single intranasal dose is highly immunogenic and protective against SARS-CoV-2 challenge in the hamster model, the most robust SARS-CoV-2 challenge model available. Based on these results, B/HPIV3/S-2P represents a promising vaccine candidate for clinical evaluation as a pediatric vaccine for intranasal immunization against HPIV3 and SARS-CoV-2. Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts toward control of COVID-19. We developed a live intranasal vector vaccine for infants and children against COVID-19 based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) that express the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as B/HPIV3 in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2–neutralizing antibodies (12-fold higher), serum IgA and IgG to SARS-CoV-2 S protein (5-fold and 13-fold), and IgG to the receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with 104.5 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 106.6 TCID50/g in lungs and 107 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P–immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S and B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2.
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影响因子：
3
作者：
Espitia CM;Zhao W;Saldarriaga O;Osorio Y;Harrison LM;Cappello M;Travi BL;Melby PC
通讯作者：
Melby PC
DOI：
10.1534/g3.118.200144
发表时间：
2018-07-02
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Edie S;Zaghloul NA;Leitch CC;Klinedinst DK;Lebron J;Thole JF;McCallion AS;Katsanis N;Reeves RH
通讯作者：
Reeves RH
影响因子：
3.7
作者：
Durbin, AP;Hall, SL;Murphy, BR
通讯作者：
Murphy, BR
影响因子：
5.4
作者：
Liang, Bo;Ngwuta, Joan O.;Munir, Shirin
通讯作者：
Munir, Shirin
影响因子：
82.9
作者：
He, Xi;Lau, Eric H. Y.;Leung, Gabriel M.
通讯作者：
Leung, Gabriel M.