Prime-boost Vaccination Strategy Research Articles

Reassortment incompetent live attenuated and replicon influenza vaccines provide improved protection against influenza in piglets

Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.

Durability of the Effectiveness of Heterologous COVID-19 Vaccine Regimens in Thailand: Retrospective Cohort Study Using National Registration Data.

The durability of heterologous COVID-19 vaccine effectiveness (VE) has been primarily studied in high-income countries, while evaluation of heterologous vaccine policies in low- and middle-income countries remains limited. We aimed to evaluate the duration during which the VE of heterologous COVID-19 vaccine regimens in mitigating serious outcomes, specifically severe COVID-19 and death following hospitalization with COVID-19, remains over 50%. We formed a dynamic cohort by linking records of Thai citizens aged ≥18 years from citizen vital, COVID-19 vaccine, and COVID-19 cases registry databases between May 2021 and July 2022. Encrypted citizen identification numbers were used to merge the data between the databases. This study focuses on 8 common heterologous vaccine sequences: CoronaVac/ChAdOx1, ChAdOx1/BNT162b2, CoronaVac/CoronaVac/ChAdOx1, CoronaVac/ChAdOx1/ChAdOx1, CoronaVac/ChAdOx1/BNT162b2, BBIBP-CorV/BBIBP-CorV/BNT162b2, ChAdOx1/ChAdOx1/BNT162b2, and ChAdOx1/ChAdOx1/mRNA-1273. Nonimmunized individuals were considered for comparisons. The cohort was stratified according to the vaccination status, age, sex, province location, month of vaccination, and outcome. Data analysis employed logistic regression to determine the VE, accounting for potential confounders and durability over time, with data observed over a follow-up period of 7 months. This study includes 52,580,841 individuals, with approximately 17,907,215 and 17,190,975 receiving 2- and 3-dose common heterologous vaccines (not mutually exclusive), respectively. The 2-dose heterologous vaccinations offered approximately 50% VE against severe COVID-19 and death following hospitalization with COVID-19 for 2 months; however, the protection significantly declined over time. The 3-dose heterologous vaccinations sustained over 50% VE against both outcomes for at least 8 months, as determined by logistic regression with durability time-interaction modeling. The vaccine sequence consisting of CoronaVac/CoronaVac/ChAdOx1 demonstrated >80% VE against both outcomes, with no evidence of VE waning. The final monthly measured VE of CoronaVac/CoronaVac/ChAdOx1 against severe COVID-19 and death following hospitalization at 7 months after the last dose was 82% (95% CI 80.3%-84%) and 86.3% (95% CI 83.6%-84%), respectively. In Thailand, within a 7-month observation period, the 2-dose regimens could not maintain a 50% VE against severe and fatal COVID-19 for over 2 months, but all of the 3-dose regimens did. The CoronaVac/CoronaVac/ChAdOx1 regimen showed the best protective effect against severe and fatal COVID-19. The estimated durability of 50% VE for at least 8 months across all 3-dose heterologous COVID-19 vaccine regimens supports the adoption of heterologous prime-boost vaccination strategies, with a primary series of inactivated virus vaccine and boosting with either a viral vector or an mRNA vaccine, to prevent similar pandemics in low- and middle-income countries.

A superior heterologous prime-boost vaccination strategy against COVID-19: A bivalent vaccine based on yeast-derived RBD proteins followed by a heterologous vaccine.

Various vaccines have been challenged by SARS-CoV-2 variants. Here, we reported a yeast-derived recombinant bivalent vaccine (Bivalent wild-type [Wt]+De) based on the wtand Delta receptor-binding domain (RBD). Yeast derived RBD proteins based on the wtand Delta mutant were used as the prime vaccine. It was found that, in the presence of aluminium hydroxide (Alum) and unmethylated CpG-oligodeoxynucleotides (CpG) adjuvants, more cross-protective immunity against SARS-CoV-2 prototype and variants were elicited by bivalent vaccine than monovalent wtRBD or Delta RBD. Furthermore, a heterologous boosting strategy consisting of two doses of bivalent vaccines followed by one dose adenovirus vectored vaccine exhibited cross-neutralization capacity and specific T cell responses against Delta and Omicron (BA.1 and BA.4/5) variants in mice, superior to a homologous vaccination strategy. This study suggested that heterologous prime-boost vaccination with yeast-derived bivalent protein vaccine could be a potential approach to address the challenge of emerging variants.

Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 Tcells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 Tcell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 Tcells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

An HIV-1/HIV-2 Chimeric Envelope Glycoprotein Generates Binding and Neutralising Antibodies against HIV-1 and HIV-2 Isolates.

The development of immunogens that elicit broadly reactive neutralising antibodies (bNAbs) is the highest priority for an HIV vaccine. We have shown that a prime-boost vaccination strategy with vaccinia virus expressing the envelope glycoprotein gp120 of HIV-2 and a polypeptide comprising the envelope regions C2, V3 and C3 elicits bNAbs against HIV-2. We hypothesised that a chimeric envelope gp120 containing the C2, V3 and C3 regions of HIV-2 and the remaining parts of HIV-1 would elicit a neutralising response against HIV-1 and HIV-2. This chimeric envelope was synthesised and expressed in vaccinia virus. Balb/c mice primed with the recombinant vaccinia virus and boosted with an HIV-2 C2V3C3 polypeptide or monomeric gp120 from a CRF01_AG HIV-1 isolate produced antibodies that neutralised >60% (serum dilution 1:40) of a primary HIV-2 isolate. Four out of nine mice also produced antibodies that neutralised at least one HIV-1 isolate. Neutralising epitope specificity was assessed using a panel of HIV-1 TRO.11 pseudoviruses with key neutralising epitopes disrupted by alanine substitution (N160A in V2; N278A in the CD4 binding site region; N332A in the high mannose patch). The neutralisation of the mutant pseudoviruses was reduced or abolished in one mouse, suggesting that neutralising antibodies target the three major neutralising epitopes in the HIV-1 envelope gp120. These results provide proof of concept for chimeric HIV-1/HIV-2 envelope glycoproteins as vaccine immunogens that can direct the antibody response against neutralising epitopes in the HIV-1 and HIV-2 surface glycoproteins.

Safety and efficacy of COVID-19 prime-boost vaccinations: Homologous BBIBP-CorV versus heterologous BNT162b2 boosters in BBIBP-CorV-primed individuals.

Booster vaccine doses against SARS-CoV-2 have been advocated to address evidence of waning immunity, breakthrough infection, and the emergence of immune-evasive variants. A heterologous prime-boost vaccine strategy may offer advantages over a homologous approach, but the safety and efficacy of this approach with the mRNA vaccine BNT162b2 (BNT: Pfizer) and inactivated BBIBP-CorV (BBIBT: Sinopharm) vaccines have not been studied. We conducted a non-randomized, non-blinded phase II observational community trial acrossBahrain, investigating the reactogenic and immunogenic responseof participants who had previously received two doses of BBIBP, followed by a third booster dose of either BBIBP (homologous booster) or BNT (heterologous booster). Immunogenicity through serological statuswas determined at baseline and on the following 8thweek. Reactogenicity data (safety and adverse events) were collected throughout study period, in addition to participant-led electronic journaling. 305 participants (152 BBIBP and 153 BNT booster) were enrolled in the study,with 246 (127 BBIBP and 119 BNT booster) included in the final analysis. There was a significant increase in anti-SARS-CoV-2 antibody levels post booster administration in both groups; however, the heterologous BNT arm demonstrated a significantly larger mean increase in the level of spike (S) antigen-specific antibodies (32.7-fold increase versus 2.6, p<0.0001) and sVNT neutralising antibodies (3.4-fold increase versus 1.8, p<0.0001), whereas the homologous arm demonstrated a significant increase in the levels of nucleocapsid (N) antigen-specific antibodies (3.8-fold increase versus none). Non-serious adverse events (injection site pain, fever, and fatigue) were more commonly reported in the heterologous arm, but no serious adverse events occurred. Heterologous prime-boost vaccination with the mRNA BNT162b2 (Pfizer) vaccine in those who had received two doses of inactivated virus BBIBP-CorV (Sinopharm) vaccine demonstrated a more robust immune response against SARS-CoV-2 than the homologous BBIBP booster and appears safe and well tolerated. Clinical Trial Registry Number (ClinicalTrials.gov): NCT04993560.

Heterologous prime-boost cellular vaccination induces potent antitumor immunity against triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive and hard-to-treat subtype of breast cancer, affecting 10-20% of all women diagnosed with breast cancer. Surgery, chemotherapy and hormone/Her2 targeted therapies are the cornerstones of treatment for breast cancer, but women with TNBC do not benefit from these treatments. Although the prognosis is dismal, immunotherapies hold significant promise in TNBC, even in wide spread disease because TNBC is infiltrated with more immune cells. This preclinical study is proposing to optimize an oncolytic virus-infected cell vaccine (ICV) based on a prime-boost vaccination strategy to address this unmet clinical need. We used various classes of immunomodulators to improve the immunogenicity of whole tumor cells in the prime vaccine, followed by their infection with oncolytic Vesicular Stomatitis Virus (VSVd51) to deliver the boost vaccine. For in vivo studies, we compared the efficacy of a homologous prime-boost vaccination regimen to a heterologous strategy by treating 4T1 tumor bearing BALB/c mice and further by conducting re-challenge studies to evaluate immune memory responses in surviving mice. Due to the aggressive nature of 4T1 tumor spread (akin to stage IV TNBC in human patients), we also compared early surgical resection of primary tumors versus later surgical resection combined with vaccination. In vitro results demonstrated that immunogenic cell death (ICD) markers and pro-inflammatory cytokines were released at the highest levels following treatment of mouse 4T1 TNBC cells with oxaliplatin chemotherapy and influenza vaccine. These ICD inducers also contributed towards higher dendritic cell recruitment and activation. With the top ICD inducers at hand, we observed that treatment of TNBC-bearing mice with the influenza virus-modified prime vaccine followed by VSVd51 infected boost vaccine resulted in the best survival. Furthermore, higher frequencies of both effector and central memory T cells along with a complete absence of recurrent tumors were observed in re-challenged mice. Importantly, early surgical resection combined with prime-boost vaccination led to improved overall survival in mice. Taken together, this novel cancer vaccination strategy following early surgical resection could be a promising therapeutic avenue for TNBC patients.

Persistent T cell-mediated immune responses against Omicron variants after the third COVID-19 mRNA vaccine dose.

The prime-boost COVID-19 mRNA vaccination strategy has proven to be effective against severe COVID-19 disease and death. However, concerns have been raised due to decreasing neutralizing antibody levels after COVID-19 vaccination and due to the emergence of new immuno-evasive SARS-CoV-2 variants that may require additional booster vaccinations. In this study, we analyzed the humoral and cell-mediated immune responses against the Omicron BA.1 and BA.2 subvariants in Finnish healthcare workers (HCWs) vaccinated with three doses of COVID-19 mRNA vaccines. We used enzyme immunoassay and microneutralization test to analyze the levels of SARS-CoV-2 specific IgG antibodies in the sera of the vaccinees and the in vitro neutralization capacity of the sera. Activation induced marker assay together with flow cytometry and extracellular cytokine analysis was used to determine responses in SARS-CoV-2 spike protein stimulated PBMCs. Here we show that within the HCWs, the third mRNA vaccine dose recalls both humoral and T cell-mediated immune responses and induces high levels of neutralizing antibodies against Omicron BA.1 and BA.2 variants. Three weeks after the third vaccine dose, SARS-CoV-2 wild type spike protein-specific CD4+ and CD8+ T cells are observed in 82% and 71% of HCWs, respectively, and the T cells cross-recognize both Omicron BA.1 and BA.2 spike peptides. Although the levels of neutralizing antibodies against Omicron BA.1 and BA.2 decline 2.5 to 3.8-fold three months after the third dose, memory CD4+ T cell responses are maintained for at least eight months post the second dose and three months post the third vaccine dose. We show that after the administration of the third mRNA vaccine dose the levels of both humoral and cell-mediated immune responses are effectively activated, and the levels of the spike-specific antibodies are further elevated compared to the levels after the second vaccine dose. Even though at three months after the third vaccine dose antibody levels in sera decrease at a similar rate as after the second vaccine dose, the levels of spike-specific CD4+ and CD8+ T cells remain relatively stable. Additionally, the T cells retain efficiency in cross-recognizing spike protein peptide pools derived from Omicron BA.1 and BA.2 subvariants. Altogether our results suggest durable cellmediated immunity and protection against SARS-CoV-2.

Potential Interference of Maternally Derived Antibodies (MDA) of Commercial Broiler Chicks on the Efficacy of Different Vectored –ND Vaccines

Maternally derived antibodies (MDA) are a major problem for the application of NDV-vectored vaccines in commercial chickens with high levels of MDA, which could impair its efficacy. In this study, we assessed the effectiveness of different commercial vectored ND in broilers chicks with MDA against local heterologous NDV genotype VII. For this purpose, Two hundred and forty one day old chicks were divided into eight groups (30 chicks/group) (G1, G2, G3, G4, G5, G6 and G7) vaccinated with four different recombinant ND vaccines using different vaccination scheme. In addition, Group 8 (30 chicks) kept as a control non-vaccinated group. Efficacy of this type of vaccine is evaluated routinely by vaccination-challenge test. ELISA test were used for detection antibodies from collected sera of all chickens groups. Challenge test were applied at 31th day's old age of chickens. To calculate viral Shedding, cloacal swabs were collected from all groups and examined by real time RT-PCR. Obtained results for G8 (control) was recorded high antibody titer at one day but decreased gradually till become negative at 24 day old. While vaccinated groups exhibited antibody titers at 38 days old which were 3.6, 3.7, 4, 3.7, 3.66, 3.77, and 3.3 for G1, G2, G3, G4, G5, G6 and G7, respectively. Protection% of vectored ND vaccines groups ranged from 80 to 95 % despite inactivated ND vaccine recorded 60%. It was concluded that the recombinant ND vectored vaccines more potent than inactivated one in broiler chickens with MDA. Administration of rFowl-Pox+ND vaccine at 10 day exhibited higher immune response and conferred more protection and reduction of viral shedding in comparison to vaccinated at hatchery. Using rHVT+ND vaccine in one day old chicks confer optimum immune response and protection% in presence of MDA. Prime-boost vaccination strategy can overcome the problem of MDA in broiler chickens vaccination. So, it was recommended to measure the level of MDA in offspring to determine the ideal time for vaccination

A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19

Heterologous prime-boost COVID-19 vaccine strategy may facilitate mass COVID-19 immunization. We reported early immunogenicity and safety outcomes of heterologous immunization with a viral vector vaccine (ChAdOx1) and a spike-2P subunit vaccine (MVC-COV1901) in a participant-blinded, randomized, non-inferiority trial (NCT05054621). A total of 100 healthy adults aged 20–70 years having the first dose of ChAdOx1 were 1:1 randomly assigned to receive a booster dose either with ChAdOx1 (n = 50) or MVC-COV1901 (n = 50) at an interval of 4–6 or 8–10 weeks. At day 28 post-boosting, the neutralizing antibody geometric mean titer against wild-type SARS-CoV-2 in MVC-COV1901 recipients (236 IU/mL) was superior to that in ChAdOx1 recipients (115 IU/mL), with a GMT ratio of 2.1 (95% CI, 1.4 to 2.9). Superiority in the neutralizing antibody titer against Delta variant was also found for heterologous MVC-COV1901 immunization with a GMT ratio of 2.6 (95% CI, 1.8 to 3.8). Both spike-specific antibody-secreting B and T cell responses were substantially enhanced by the heterologous schedule. Heterologous boosting was particularly prominent at a short prime-boost interval. No serious adverse events occurred across all groups. The findings support the use of heterologous prime-boost with ChAdOx1 and protein-based subunit vaccines.

Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency.

A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically related, antibody-sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody-sensitive viruses is a promising approach to inducing potent bNAbs in humans.

Comparative characterization of antibody responses induced by Ad5-vectored spike proteins of emerging SARS-CoV-2 VOCs

Highly divergent SARS-CoV-2 variants have continuously emerged and spread around the world, and updated vaccines and innovative vaccination strategies are urgently needed to address the global SARS-COV2 pandemic. Here, we established a series of Ad5-vectored SARS-CoV-2 variant vaccines encoding multiple spike proteins derived from the Alpha, Beta, Gamma, Epsilon, Kappa, Delta and Omicron lineages and analyzed the antibody immune responses induced by single-dose and prime-boost vaccination strategies against emerging SARS-CoV-2 variants of concern (VOCs). Single-dose vaccination with SARS-CoV-2 variant vaccines tended to elicit the optimal self-matched neutralizing effects, and Ad5-B.1.351 produced more broad-spectrum cross-neutralizing antibodies against diverse variants. In contrast, prime-boost vaccination further strengthened and broadened the neutralizing antibody responses against highly divergent SARS-CoV-2 variants. The heterologous administration of Ad5-B.1.617.2 and Ad5-B.1.429 to Ad5-WT-primed mice resulted in superior antibody responses against most VOCs. In particular, the Omicron spike could only stimulate self-matched neutralizing antibodies with infrequent cross-reactivities to other variants used in single-dose vaccination strategies; moreover, with prime-boost regimens, this vaccine elicited an optimal specific neutralizing antibody response to Omicron, and prompted cross-antibody responses against other VOCs that were very similar to those obtained with Ad5-WT booster. Overall, this study delineated the unique characteristics of antibody responses to the SARS-CoV-2 VOC spikes with the single-dose or prime-boost vaccination strategies and provided insight into the vaccine development of next SARS-CoV-2 VOCs.

Virus-Like Particles Are Efficient Tools for Boosting mRNA-Induced Antibodies.

mRNA based vaccines against COVID-19 have proven most successful at keeping SARS-CoV-2 pandemic at bay in many countries. Recently, there is an increased interest in heterologous prime-boost vaccination strategies for COVID-19 to maintain antibody responses for the control of continuously emerging SARS-CoV-2 variants of concern (VoCs) and to overcome other obstacles such as supply shortage, costs and reduced safety issues or inadequatly induced immune-responses. In this study, we investigated the antibody responses induced by heterologous prime-boost with vaccines based on mRNA and virus-like particles (VLPs). The VLP-based mCuMVTT-RBM vaccine candidate and the approved mRNA-1273 vaccine were used for this purpose. We find that homologous prime boost regimens with either mRNA or VLP induced high levels of high avidity antibodies. Optimal antibody responses were, however, induced by heterologous regimens both for priming with mRNA and boosting with VLP and vice versa, priming with VLP and boosting with mRNA. Thus, heterologous prime boost strategies may be able to optimize efficacy and economics of novel vaccine strategies.

PLGA particle vaccination elicits resident memory CD8 T cells protecting from tumors and infection

The essential role of tissue-resident memory T cells (TRM cells) in offering protection from recurring infections and malignant tumors is becoming increasingly clear. Due to their presence in many barrier tissues, TRM cells are ideally located to rapidly respond to re-encountered pathogens. Moreover, a host of studies has shown that the quantity of TRM cells correlates with increased survival rates in cancer patients. Therefore, vaccination strategies which induce a strong and sustained TRM cell response are particularly promising. In this study we show that this response can be induced by employing a prime-boost vaccination strategy using biodegradable poly (D,L-lactide-co-glycolide) microspheres (PLGA MS). A subcutaneous prime immunization followed by an intranasal boost immunization led to a strong TRM cell response in the lungs of mice 6 days after the boost vaccination. Although numbers subsequently declined, TRM cells were still detectable 60 days after vaccination. Functionally, we observed that immunized mice were protected from lung metastasis formation and tumor growth in a B16Bl6 melanoma model. Furthermore, the TRM cells induced by PLGA MS immunization provided protection in an infectious model using a recombinant influenza A virus (IAV). Taken together, these results show that the ability of PLGA MS to induce a strong TRM cell response further supports their use as a potent vaccine.

CD4+ T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy

BackgroundAntitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+ T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from...

Efficacy of the NS1-truncated live attenuated influenza virus vaccine for swine against infection with viruses of major North American and European H3N2 lineages

Control of swine influenza A virus (swIAV) in North America and Europe is complicated because multiple antigenically distinct swIAV strains co-circulate in the field, and no vaccine is available that can provide broad cross-protection against all these swIAVs. In 2017, the first live attenuated influenza vaccine (LAIV) for swine was licensed in the US. The non-structural protein 1 (NS1)-truncated cluster I H3N2 strain A/swine/Texas/4199-2/98 NS1del126 (TX98 LAIV) in this vaccine provides partial cross-protection against heterologous North American cluster II and IV H3N2 swIAV strains. Its efficacy against European or more recent North American H3N2 lineages remains to be investigated. In this study, we evaluated the level of cross-protection against heterologous IAVs representative of the major H3N2 swIAV lineages in Europe and North America. TX98 LAIV prevented both nasal shedding and replication in the lungs of a North American cluster IV H3N2 swIAV for 2/4 pigs, prevented considerable nasal shedding of a North American novel human-like H3N2 swIAV for 2/4 pigs, and reduced replication of a European H3N2 swIAV in the lower respiratory tract to minimal titers for 1/3 pigs. Although TX98 LAIV elicited neutralizing antibodies against the homologous virus in serum and to a lesser extent in nose and lungs, no significant cross-reactive antibody titers against the heterologous swIAVs were detected. Partial cross-protection therefore likely relies on cellular and mucosal immune responses against conserved parts of the swIAV proteins. Since TX98 LAIV can offer partial protection against a broad range of H3N2 swIAVs, it might be a suitable priming vaccine for use in a heterologous prime-boost vaccination strategy.

A Thermostable Oral SARS-CoV-2 Vaccine Induces Mucosal and Protective Immunity.

An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (eVLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made eVLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated eVLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered eVLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.

Antibody Response of Combination of BNT162b2 and CoronaVac Platforms of COVID-19 Vaccines against Omicron Variant.

By vaccinating SARS-CoV-2 naïve individuals who have already received two doses of COVID-19 vaccines, we aimed to investigate whether a heterologous prime-boost strategy, using vaccines of different platforms as the booster dose, can enhance the immune response against SARS-CoV-2 virus variants. Participants were assigned into four groups, each receiving different combination of vaccinations: two doses of BNT162b2 followed by one dose of BNT162b2 booster (B-B-B); Combination of BNT162b2 (first dose) and CoronaVac (second dose) followed by one dose of BNT162b2 booster (B-C-B); two doses of CoronaVac followed by one dose of CoronaVac booster (C-C-C); two doses of CoronaVac followed by one dose of BNT162b2 booster (C-C-B). The neutralizing antibody in sera against the virus was determined with live virus microneutralization assay (vMN). The B-B-B group and C-C-B group demonstrated significantly higher immunogenicity against SARS-CoV-2 Wild type (WT), Beta variant (BV) and Delta variant (DV). In addition, the B-B-B group and C-C-B group showed reduced but existing protection against Omicron variant (OV). Moreover, A persistent rise in vMN titre against OV was observed 3 days after booster dose. Regarding safety, a heterologous prime-boost vaccine strategy is well tolerated. In this study, it was demonstrated that using vaccines of different platforms as booster dose can enhance protection against SARS-CoV-2 variants, offering potent neutralizing activity against wild-type virus (WT), Beta variant (BV), Delta variant (DV) and some protection against the Omicron variant (OV). In addition, a booster mRNA vaccine results in a more potent immune response than inactivated vaccine regardless of which platform was used for prime doses.

A vesicular stomatitis virus-based prime-boost vaccination strategy induces potent and protective neutralizing antibodies against SARS-CoV-2.

The development of safe and effective vaccines to prevent SARS-CoV-2 infections remains an urgent priority worldwide. We have used a recombinant vesicular stomatitis virus (rVSV)-based prime-boost immunization strategy to develop an effective COVID-19 vaccine candidate. We have constructed VSV genomes carrying exogenous genes resulting in the production of avirulent rVSV carrying the full-length spike protein (SF), the S1 subunit, or the receptor-binding domain (RBD) plus envelope (E) protein of SARS-CoV-2. Adding the honeybee melittin signal peptide (msp) to the N-terminus enhanced the protein expression, and adding the VSV G protein transmembrane domain and the cytoplasmic tail (Gtc) enhanced protein incorporation into pseudotype VSV. All rVSVs expressed three different forms of SARS-CoV-2 spike proteins, but chimeras with VSV-Gtc demonstrated the highest rVSV-associated expression. In immunized mice, rVSV with chimeric S protein-Gtc derivatives induced the highest level of potent neutralizing antibodies and T cell responses, and rVSV harboring the full-length msp-SF-Gtc proved to be the superior immunogen. More importantly, rVSV-msp-SF-Gtc vaccinated animals were completely protected from a subsequent SARS-CoV-2 challenge. Overall, we have developed an efficient strategy to induce a protective response in SARS-CoV-2 challenged immunized mice. Vaccination with our rVSV-based vector may be an effective solution in the global fight against COVID-19.

Using a Prime-Boost Vaccination Strategy That Proved Effective for High Resolution Epitope Mapping to Characterize the Elusive Immunogenicity of Survivin.

Simple SummaryThe generation of tumor-specific T cells remains a pillar of modern cancer immunotherapy. Exogenous vaccines often rely on targeting tumor-associated antigens. The anti-apoptotic protein survivin has been deemed a high priority target due to its overexpression in a wide variety of tumor types. To support the analysis of tumor-associated T cell responses, optimization of epitope mapping would be valuable. A heterologous prime-boost vaccination strategy was designed to target survivin to induce anti-tumor immune responses. However, survivin-specific T cell responses could not be detected in mice. Potential mechanisms to explain this failure were explored. To confirm the robustness of the vaccination platform, enhanced green fluorescent protein (eGFP) was targeted since it has been defined as a protein with relatively low immunogenicity. In this context the vaccination strategy uncovered novel T cell epitopes from eGFP in two strains of mice. This research highlighted the utility of the vaccine platform to triage potential target antigens based on their immunogenicity.Survivin is a member of the inhibitor of apoptosis family of proteins and has been reported to be highly expressed in a variety of cancer types, making it a high priority target for cancer vaccination. We previously described a heterologous prime-boost strategy using a replication-deficient adenovirus, followed by an oncolytic rhabdovirus that generates unprecedented antigen-specific T cell responses. We engineered each vector to express a mutated version of full-length murine survivin. We first sought to uncover the complete epitope map for survivin-specific T cell responses in C57BL/6 and BALB/c mice by flow cytometry. However, no T cell responses were detected by intracellular cytokine staining after re-stimulation of T cells. Survivin has been found to be expressed by activated T cells, which could theoretically cause T cell-mediated killing of activated T cells, known as fratricide. We were unable to recapitulate this phenomenon in experiments. Interestingly, the inactivated survivin construct has been previously shown to directly kill tumor cells in vitro. However, there was no evidence in our models of induction of death in antigen-presenting cells due to treatment with a survivin-expressing vector. Using the same recombinant virus-vectored prime-boost strategy targeting the poorly immunogenic enhanced green fluorescent protein proved to be a highly sensitive method for mapping T cell epitopes, particularly in the context of identifying novel epitopes recognized by CD4+ T cells. Overall, these results suggested there may be unusually robust tolerance to survivin in commonly used mouse strains that cannot be broken, even when using a particularly potent vaccination platform. However, the vaccination method shows great promise as a strategy for identifying novel and subdominant T cell epitopes.