LNP-CpG ODN-adjuvanted varicella-zoster virus glycoprotein E induced comparable levels of immunity with Shingrix™ in VZV-primed mice.

Latent varicella-zoster virus (VZV) may be reactivated to cause herpes zoster, which affects one in three people during their lifetime. The currently available subunit vaccine Shingrix™ is superior to the attenuated vaccine Zostavax® in terms of both safety and efficacy, but the supply of its key adjuvant component QS21 is limited. With ionizable lipid nanoparticles (LNPs) that were recently approved by the FDA for COVID-19 mRNA vaccines as carriers, and oligodeoxynucleotides containing CpG motifs (CpG ODNs) approved by the FDA for a subunit hepatitis B vaccine as immunostimulators, we developed a LNP vaccine encapsulating VZV-glycoprotein E (gE) and CpG ODN, and compared its immunogenicity with Shingrix™ in C57BL/6J mice. The results showed that the LNP vaccine induced comparable levels of gE-specific IgG antibodies to Shingrix™ as determined by enzyme-linked immunosorbent assay (ELISA). Most importantly, the LNP vaccine induced comparable levels of cell-mediated immunity (CMI) that plays decisive roles in the efficacy of zoster vaccines to Shingrix™ in a VZV-primed mouse model that was adopted for preclinical studies of Shingrix™. Number of IL-2 and IFN-γ secreting splenocytes and proportion of T helper 1 (Th1) cytokine-expressing CD4+ T cells in LNP-CpG-adjuvanted VZV-gE vaccinated mice were similar to that of Shingrix™ boosted mice. All of the components in this LNP vaccine can be artificially and economically synthesized in large quantities, indicating the potential of LNP-CpG-adjuvanted VZV-gE as a more cost-effective zoster vaccine.

A network analysis of anxiety and depression symptoms among Chinese nurses in the late stage of the COVID-19 pandemic.

Background: Nurses are at high risk for depression and anxiety symptoms after the outbreak of the COVID-19 pandemic. We aimed to assess the network structure of anxiety and depression symptoms among Chinese nurses in the late stage of this pandemic. Method: A total of 6,183 nurses were recruited across China from Oct 2020 to Apr 2021 through snowball sampling. We used Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder scale-7 (GAD-7) to assess depression and anxiety, respectively. We used the Ising model to estimate the network. The index "expected influence" and "bridge expected influence" were applied to determine the central symptoms and bridge symptoms of the anxiety-depression network. We tested the stability and accuracy of the network via the case-dropping procedure and non-parametric bootstrapping procedure. Result: The network had excellent stability and accuracy. Central symptoms included "restlessness", "trouble relaxing", "sad mood", and "uncontrollable worry". "Restlessness", "nervous", and "suicidal thoughts" served as bridge symptoms. Conclusion: Restlessness emerged as the strongest central and bridge symptom in the anxiety-depression network of nurses. Intervention on depression and anxiety symptoms in nurses should prioritize this symptom.

Effectiveness of a Brief Mindfulness-Based Intervention of "STOP touching your face" During the COVID-19 Pandemic: a Randomized Controlled Trial.

Objectives: Avoiding touching the eyes, nose, and mouth (T-zone) is a strategy to reduce the spread of COVID-19. This study evaluated the effectiveness of a brief mindfulness-based intervention (MBI) named "STOP (Stop, Take a Breath, Observe, Proceed) touching your face" for reducing face-touching behavior. Methods: In this online-based, two-arm, wait-list, randomized controlled trial, eligible participants were randomly assigned to the intervention (n = 545) or control group (n = 545). The results of 60-min self-monitoring of face-touching behavior were reported before and after the intervention. Reduction of the percentage of T-zone touching was the primary outcome, and reduction of face-touching frequency was a key secondary outcome. Outcomes were analyzed on an intention-to-treat (ITT) basis with a complete case analysis (CCA). Results: ITT analysis revealed that the percentage of T-zone touching was significantly reduced by 8.1% in the intervention group (from 81.1 to 73.0%, RR = 0.901, OR = 0.631, RD = - 0.081, p = 0.002), and insignificantly reduced by 0.6% in the control group (from 80.0 to 79.4%, p = 0.821). Fewer participants performed T-zone touching in the intervention group than in the control group (73.0% vs. 79.4%, RR = 0.919, OR = 0.700, RD = - 0.064, p = 0.015) after the intervention, and there was a greater reduction of T-zone touching frequency in the intervention group than in the control group [mean ± SD: 1.7 ± 5.13 vs. 0.7 ± 3.98, mean difference (95% CI): 1.03 (0.48 to 1.58), p < 0.001, Cohen's d = - 0.218]. The above results were further confirmed by CCA. Conclusions: This brief mindfulness-based intervention was potentially effective at reducing the spread of COVID-19 and could be further investigated as an intervention for preventing other infectious diseases spread by hand-to-face touching. Trial Registration: ClinicalTrials.gov NCT04330352. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02019-x.

Operation of the anti-doping laboratory for the Beijing 2022 Olympic and Paralympic Winter Games.

Doping analysis with a fast-turnaround-time reporting of 24/48 h is a "traditional" requirement for major competitions such as the Olympic Games, which require tremendously increased allocation of resources, especially during the COVID-19 pandemic. The "Closed-Loop" concept and operation mode established by the Beijing Organizing Committee for the 2022 Olympic and Paralympic Winter Games (BOCOG) provided a relatively isolated environment to non-Games-related civilians. To maintain this system, more than 200 persons were included as supporting crew of the laboratory with massive logistic resources allocated. The National Anti-Doping Laboratory in Beijing carried out the analysis mission of the Beijing 2022 Olympic and Paralympic Winter Games. During the Winter Olympics, 3165 samples were analyzed, whereas during the Paralympics, 679 samples were analyzed. The workforce accomplishing this work was composed of 36 domestic analysts, 20 international experts from other World Anti-Doping Agency-accredited laboratories, 61 university students with suitable majors, and 12 on-site instrumental engineers. This article summarizes the achievements from the laboratory's preparation phase; in-Game operational details such as instruments, methods, workforces, and facility; and the Quality Assurance measures to maintain the integrity and correctness of results reported to the Result Management Authority, with the effect of the pandemic and "Closed-Loop" situation during the whole process highlighted.

Breadth of SARS-CoV-2 neutralization and protection induced by a nanoparticle vaccine.

Coronavirus vaccines that are highly effective against current and anticipated SARS-CoV-2 variants are needed to control COVID-19. We previously reported a receptor-binding domain (RBD)-sortase A-conjugated ferritin nanoparticle (scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected non-human primates (NHPs) from SARS-CoV-2 WA-1 infection. Here, we find the RBD-scNP induced neutralizing antibodies in NHPs against pseudoviruses of SARS-CoV and SARS-CoV-2 variants including 614G, Beta, Delta, Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5, and a designed variant with escape mutations, PMS20. Adjuvant studies demonstrate variant neutralization titers are highest with 3M-052-aqueous formulation (AF). Immunization twice with RBD-scNPs protect NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protect mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect animals from multiple different SARS-related viruses. Such a vaccine could provide broad immunity to SARS-CoV-2 variants.

The prevalence and risk factors of mental problems in medical students during COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis and systematic review aimed to evaluate the global prevalence and risk factors of mental problems (i.e., depression, anxiety, stress, sleep disorder, posttraumatic stress disorder (PTSD), burnout, psychological distress, and suicidal ideation) among medical students during the COVID-19 pandemic. METHOD: We searched PubMed, Embase, Web of Science, psycARTICLES, PsycINFO, CNKI, and Wan Fang for studies on the prevalence of mental problems among medical students from January 1, 2020, to April 1, 2022. The pooled prevalence was calculated by random-effect models. We performed a narrative review to identify the risk factors. RESULTS: The meta-analysis included 201 studies (N = 198,000). The prevalence of depression (41 %, 95 % CI, 37-45 %,), anxiety (38 %,95 % CI, 34 %-42 %), stress (34 %, 95 % CI, 27 %-42 %), sleep disorder (52 %, 95 % CI, 44 %-60 %), psychological distress (58 %, 95 % CI, 51 %-65 %), PTSD (34 %, 95 % CI, 22 %-46 %), suicidal ideation (15 %, 95 % CI, 11 %-18 %) and burnout (38 %, 95 % CI, 25 %-50 %) was high. The major risk factors were being female, being junior or preclinical students, exposure to COVID-19, academic stress, psychiatric or physical disorders history, economic trouble, fear of education impairment, online learning trouble, fear of infection, loneliness, low physical activity, low social support, problematic internet or smartphone use, and young age. LIMITATIONS: Most studies were cross-sectional. Few studies provided a reasonable response rate, suggesting potential selection bias. CONCLUSIONS: The study demonstrated a high prevalence and risk factors for mental problems during COVID-19, calling for mental health services. Our findings are valuable for college and health authorities to identify high-risk students and provide targeted intervention.

Online public attention toward allergic rhinitis in Wuhan, China: Infodemiology study using Baidu index and meteorological data.

Background: With the popularization of the Internet and medical knowledge, more and more people are learning about allergic rhinitis (AR) on the Internet. Objective: This study aims to analyze the epidemiological characteristics and online public attention to AR in Wuhan, China, utilizing the most popular search engine in mainland China and meteorological data of Wuhan. Methods: To study the Internet attention and epidemiological characteristics of AR in Wuhan, the search volume (SV) of "Allergic Rhinitis" in Mandarin and AR-related search terms from 1 January 2014 through 31 December 2021 were recorded. For user interest, the search and demand data were collected and analyzed. Results: The yearly average Baidu SV of AR in both Wuhan and China increased year by year but began to decline gradually after the COVID-19 pandemic. Baidu SV of AR in Wuhan exhibited significant seasonal variation, with the first peak was from March to May and the second peak occurring between September and October. Correlation analysis revealed a moderate positive correlation between the monthly average SV of "Allergic Rhinitis" and "Mites" and "Mites + Pollen Allergy" in Wuhan, a weak positive correlation between the monthly average SV of "Allergic Rhinitis" and "Pollen Allergy," and a positive correlation between monthly SV of "Allergic Rhinitis" and the meteorological index of pollen allergy (MIPA). Conclusion: The attention given to the topic on the internet, as measured by the search volume, was reflective of the situation in Wuhan, China. It has the potential to predict the epidemiological characteristics of AR and help medical professionals more effectively plan seasonal AR health education.

Ionizable Lipid Nanoparticles Enhanced the Synergistic Adjuvant Effect of CpG ODNs and QS21 in a Varicella Zoster Virus Glycoprotein E Subunit Vaccine.

Varicella zoster virus (VZV) causes two diseases: varicella upon primary infection and herpes zoster when latent viruses in the sensory ganglia reactivate. While varicella vaccines depend on humoral immunity to prevent VZV infection, cell-mediated immunity (CMI), which plays a therapeutic role in the control or elimination of reactivated VZV in infected cells, is decisive for zoster vaccine efficacy. As one of the most abundant glycoproteins of VZV, conserved glycoprotein E (gE) is essential for viral replication and transmission between ganglion cells, thus making it an ideal target subunit vaccine antigen; gE has been successfully used in the herpes zoster vaccine ShingrixTM on the market. In this report, we found that ionizable lipid nanoparticles (LNPs) approved by the Food and Drug Administration (FDA) as vectors for coronavirus disease 2019 (COVID-19) mRNA vaccines could enhance the synergistic adjuvant effect of CpG oligodeoxynucleotides (CpG ODNs) and QS21 on VZV-gE, affecting both humoral immunity and CMI. Vaccines made with these LNPs showed promise as varicella vaccines without a potential risk of herpes zoster, which identifies them as a novel type of herpes zoster vaccine similar to ShingrixTM. All of the components in this LNP-CpG-QS21 adjuvant system were proven to be safe after mass vaccination, and the high proportion of cholesterol contained in the LNPs was helpful for limiting the cytotoxicity induced by QS21, which may lead to the development of a novel herpes zoster subunit vaccine for clinical application.

Th2-Oriented Immune Serum After SARS-CoV-2 Vaccination Does Not Enhance Infection In Vitro.

The relatively lower protection rate of the alum-adjuvanted inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines reminds us of the antibody-dependent enhancement (ADE) phenomenon observed in preclinical studies during the development of vaccines for Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). In this study, using the S1 segment of the SARS-CoV-2 spike protein or inactivated whole SARS-CoV-2 virus as an antigen and aluminum as an adjuvant, the risk of ADE of infection with T helper 2 (Th2)-oriented immune serum from mice (N=6) and humans (N=5) was examined in immune cell lines, which show different expression patterns of Fc receptors. Neither the immune serum from alum-adjuvanted S1 subunit vaccines nor inactivated SARS-CoV-2 vaccination enhanced SARS-CoV-2 S pseudotyped virus infection in any of the tested cell lines in vitro. Because both of these Th2-oriented immune sera could block SARS-CoV-2 infection without ADE of infection, we speculate that the lower protection rate of the inactivated SARS-CoV-2 vaccine may be attributed to the lower neutralizing antibody titers induced or the pulmonary eosinophilic immunopathology accompanied by eosinophilic infiltration in the lungs upon virus exposure. Adjustment of the immunization schedule to elevate the neutralizing antibody levels and skew adjuvants toward Th1-oriented responses may be considered to increase the efficacies of both inactivated and spike protein-based subunit SARS-CoV-2 vaccines.

Gaming in China Before the COVID-19 Pandemic and After the Lifting of Lockdowns: a Nationwide Online Retrospective Survey.

With the lockdown and social distancing during the outbreak of coronavirus disease 2019 (COVID-19), gaming has become a popular leisure activity. This study aimed to explore changes in gaming behavior after the lifting of COVID-19 lockdowns and risk factors for increased gaming behavior. This online retrospective study included 5268 gamers. A total of 5% gamers scored 32 or higher on the 9-item Internet Gaming Disorder Scale-Short-Form (IGDS9-SF), suggesting diagnosis of internet gaming disorder (IGD). Over one-third of gamers reported an increase in time spent on gaming per day after the lockdowns were lifted. Logistic regression analysis revealed that gamers who were female, students, experienced stress, or scored higher on IGDS9-SF were more likely to spend more time on gaming per day after the lifting of lockdowns. These findings highlighted the needs for more effective coping strategies or interventions to prevent excessive gaming, especially for females and students.

Mental health conditions and academic burnout among medical and non-medical undergraduates during the mitigation of COVID-19 pandemic in China.

The outbreak of the novel coronavirus disease 2019 (COVID-19) has posed a great impact on people's mental health, especially for undergraduate students. This study aimed to compare the mental health conditions and academic burnout between medical and non-medical undergraduates in China when the COVID-19 pandemic is mitigating. A cross-sectional online survey was conducted among 4,972 undergraduates between October 2020 and April 2021, when the pandemic was basically under control. The survey included basic demographics information and standardized scales to evaluate depression, anxiety, perceived stress, daytime sleepiness, alcohol abuse/dependence, quality of life, fatigue, and academic burnout. Compared with medical undergraduates, non-medical undergraduates had higher rates of moderate to severe depression symptoms (29.1% vs. 17.9%, P < 0.001), moderate to severe anxiety symptoms (19.7% vs. 8.9%, P < 0.001), alcohol abuse/dependence (16.3% vs.10.3%, P < 0.001), excessive daytime sleepiness (47.4% vs. 43.4%, P = 0.018), high perceived stress (34.7% vs. 22.2%, P < 0.001), high level of fatigue (51.8% vs. 42.2%, P < 0.001), low QOL (35.8% vs. 21.4%, P < 0.001), and higher academic burnout score (59.4 vs. 57.5, P < 0.001). Being non-medical undergraduates, depression, alcohol abuse/dependence, excessive daytime sleepiness, and high perceived stress were positively associated with academic burnout, while high QOL was negatively associated with the burnout (all P < 0.001). Excessive daytime sleepiness was the strongest predictor for academic burnout.

mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice.

The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.

Comparison of immune responses induced by two or three doses of an alum-adjuvanted inactivated SARS-CoV-2 vaccine in mice.

Waning antibodies and rapidly emerging variants are challenges for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. Adjusting existing immunization schedules and further boosting strategies are under consideration. Here, the immune responses induced by an alum-adjuvanted inactivated SARS-CoV-2 vaccine in mice were compared among immunization schedules with two or three doses. For the two-dose schedule, a 0-28-day schedule induced 5-fold stronger spike-specific IgG responses than a 0-14-day schedule, with only a slight elevation of spike-specific cellular immunity 14 days after the last immunization. A third homologous boost 2 or 5 months after the second dose for the 0-28-day schedule slightly strengthened humoral responses (1.3-fold for the 0-1-3-month schedule, and 1.8-fold for the 0-1-6-month schedule) 14 days after the last immunization. Additionally, a third homologous boost (especially with the 0-1-3-month schedule) induced significantly stronger cell-mediated immunity than both two-dose immunization schedules for all indexes tested, with a response similar to that induced by a one-dose heterologous boost with BNT162b2 in clinical trials, according to cellular immunity analysis (1.5-fold). These T cell responses were Th2 oriented, with good CD4+ and CD8+ memory. These results may offer clues for applying a homologous boosting strategy for alum-adjuvanted inactivated SARS-CoV-2 vaccines.

The efficacy of probiotics in patients with severe COVID-19.

BACKGROUND: To examine the incidence of diarrhea in severe and critical coronavirus disease 2019 (COVID-19) patients, and to observe the efficacy and prognosis of probiotic use in such patients. METHODS: A retrospective study was conducted to investigate the symptoms and incidence of diarrhea in 156 cases of COVID-19 confirmed by the First Affiliated Hospital of Zhengzhou University and the Xinyang Fifth People's Hospital, China. A total of 58 cases of severe and critical COVID-19 were identified and divided into the treatment group or the control group. The control group was given standard treatment according to the Protocols for Diagnosis and Treatment of COVID-19: Prevention, Control, Diagnosis and Management. Patients in the treatment group were administered oral probiotics as well as the standard treatment. The 2 groups were compared in terms of nutritional status (serum albumin), improvement of diarrhea symptoms, changes in inflammatory condition [procalcitonin (PCT) and C-reactive protein (CRP)], the time taken to register a negative result for respiratory tract pathogens on the nucleic acid test, and changes to white blood cell and lymphocyte cell counts. RESULTS: In this study cohort, diarrhea was detected in 15.38% (24/156) of COVID-19 patients. The incidence of diarrhea in patients with mild and moderate COVID-19 was approximately 8.16% (8/98), and the incidence of diarrhea in severe and critically ill patients was approximately 27.59% (16/58). In patients with severe and critical COVID-19, probiotic treatment obviously shortened the duration of diarrhea. Furthermore, compared with the control group, patients treated with probiotics showed a significantly reduced time to achieving a negative nucleic acid test and the inflammation indexes including PCT and CRP were significantly reduced (P<0.05). CONCLUSIONS: The incidence of diarrhea in severe and critically ill COVID-19 patients was significantly higher than that in patients with mild and moderate COVID-19. Probiotics may have a good supporting role in the treatment of patients with COVID-19 and its early application is recommended.

Effects of Varicella-Zoster Virus Glycoprotein E Carboxyl-Terminal Mutation on mRNA Vaccine Efficacy.

Glycoprotein E (gE) is one of the most abundant glycoproteins in varicella-zoster virus and plays pivotal roles in virus replication and transmission between ganglia cells. Its extracellular domain has been successfully used as an antigen in subunit zoster vaccines. The intracellular C-terminal domain was reported to be decisive for gE trafficking between the endoplasmic reticulum, trans-Golgi network and endosomes and could influence virus spread and virus titers. Considering that the trafficking and distribution of mRNA vaccine-translated gE may be different from those of gE translated against the background of the viral genome (e.g., most gE in virus-infected cells exists as heterodimers with another glycoprotein, gI,), which may influence the immunogenicity of gE-based mRNA vaccines, we compared the humoral and cellular immunity induced by LNP-encapsulated mRNA sequences encoding the whole length of gE, the extracellular domain of gE and a C-terminal double mutant of gE (mutant Y569A with original motif AYRV, which targets gE to TGN, and mutants S593A, S595A, T596A and T598A with the original motif SSTT) that were reported to enhance virus spread and elevate virus titers. The results showed that while the humoral and cellular immunity induced by all of the mRNA vaccines was comparable to or better than that induced by the AS01B-adjuvanted subunit vaccines, the C-terminal double mutant of gE showed stable advantages in all of the indicators tested, including gE-specific IgG titers and T cell responses, and could be adopted as a candidate for both safer varicella vaccines and effective zoster vaccines.

A Comparison of COVID-19 Stigma and AIDS Stigma During the COVID-19 Pandemic: A Cross-Sectional Study in China.

Objective: To understand the current situation of stigmatizing attitudes toward Coronavirus Disease 2019 (COVID-19) in China and compare it with acquired immunodeficiency syndrome (AIDS). Methods: Convenient sampling and vignette-based methods were used to recruit participants on WeChat. A demographic form and adopted stigma scale were used to collect participants' demographic information and stigmatizing attitudes toward COVID-19 and AIDS. Results: A total of 13,994 questionnaires were included in this study. A high portion of participants tend to avoid contact with individuals affected with COVID-19 (74.3%) or AIDS (59.0%), as well as their family members (70.4% for COVID-19 and 47.9% for AIDS). About half of the participants agreed that affected persons could not only cause problems to their own family but also have adverse effects on others (59.6% and 55.6% for COVID-19, 56.9 and 47.0% for AIDS). The agreements with statements about perceived stigma were similar but slightly higher than those about personal stigma in both COVID-19 and AIDS. Participants' agreements with all statements regarding personal and perceived stigma attitudes between COVID-19 and AIDS were all statistically significant (p < 0.001). Participants obtained COVID-19-related information mainly from social media (91.3%) and newspaper or television (77.1%) during the epidemic, and 61.0% of them thought information from newspapers or television was the most reliable. Conclusion: Several similarities and differences of people's attitude toward COVID-19 and AIDS were found. Avoidance, blame, and secondary discrimination to diagnosed persons and their surrounding persons were the main representations of COVID-19-related stigma. Stigma of COVID-19 had less moral link but more public panic. Experience from HIV-related stigma reduction and prevention can be applied to reduce COVID-19-related stigma.

Development of mRNA manufacturing for vaccines and therapeutics: mRNA platform requirements and development of a scalable production process to support early phase clinical trials.

The remarkable success of SARS CoV-2 mRNA-based vaccines and the ensuing interest in mRNA vaccines and therapeutics have highlighted the need for a scalable clinical-enabling manufacturing process to produce such products, and robust analytical methods to demonstrate safety, potency, and purity. To date, production processes have either not been disclosed or are bench-scale in nature and cannot be readily adapted to clinical and commercial scale production. To address these needs, we have advanced an aqueous-based scalable process that is readily adaptable to GMP-compliant manufacturing, and developed the required analytical methods for product characterization, quality control release, and stability testing. We also have demonstrated the products produced at manufacturing scale under such approaches display good potency and protection in relevant animal models with mRNA products encoding both vaccine immunogens and antibodies. Finally, we discuss continued challenges in raw material identification, sourcing and supply, and the cold chain requirements for mRNA therapeutic and vaccine products. While ultimate solutions have yet to be elucidated, we discuss approaches that can be taken that are aligned with regulatory guidance.

Waning antibodies from inactivated SARS-CoV-2 vaccination offer protection against infection without antibody-enhanced immunopathology in rhesus macaque pneumonia models.

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.

An Established Th2-Oriented Response to an Alum-Adjuvanted SARS-CoV-2 Subunit Vaccine Is Not Reversible by Sequential Immunization with Nucleic Acid-Adjuvanted Th1-Oriented Subunit Vaccines.

A recently reported parallel preclinical study between a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine and an inactivated SARS-CoV-2 vaccine adjuvanted with alum showed pulmonary immunopathology typical of eosinophil accumulation in a mouse pneumonia model for the latter, which implied a potential role of cellular immunity in the difference in the protection rate between these two forms of vaccines. For those who have been vaccinated with alum-adjuvanted subunit or inactivated SARS-CoV-2 vaccines, whether the Th2 responses that have been established and the absence of induced cellular immunity could be changed is an open question. Using two heterologous boosts with Th1-oriented CpG ODN-adjuvanted S1-based SARS-CoV-2 subunit vaccines for mice that were primed with two doses of Th2-oriented alum-adjuvanted S1-based SARS-CoV-2 subunit vaccines, we demonstrated that established Th2 orientation could not be reversed to Th1 orientation and that no cellular immunity was induced, which should have been induced if the boosting vaccines were used as the prime vaccines. These results remind us that if widely administered alum-adjuvanted SARS-CoV-2 vaccines cannot overcome the challenge of coronavirus disease 2019 (COVID-19) and that if cellular immunity is important for the efficacy of SARS-CoV-2 vaccines in the future, the choice of more powerful heterologous boosting vaccine forms that can induce cellular immunity should be considered very carefully before application.

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.