Vaccine Platform-Dependent Differential Impact on Microbiome Diversity: Potential Advantages of Protein Subunit Vaccines

<p indent="0mm">The novel coronavirus (SARS-CoV-2) caused a global pandemic, with significant distress to human health, society stability, and development. COVID-19 vaccination has played a pivotal role to control the pandemic, with multiple vaccine approaches approved globally, including inactivated recombinant protein subunits, virus-like particles, viral vectors, mRNA, and DNA vaccines. Notably, we collaborated with Anhui Zhifei longcom Biopharmaceutical Co., Ltd. to develop a COVID-19 vaccine (ZF2001) based on recombinant protein subunit platform, using a tandem-repeat dimeric form of receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as immunogen. Besides, the adenovirus vector vaccine, Ad5-nCoV (Convidecia, CanSino), developed jointly by the Chinese Academy of Military Medical Sciences and CanSino Biologics, employs a human adenovirus type 5 vector to express the full-length S protein of SARS-CoV-2. mRNA vaccines BNT162b2 (Comirnaty), developed by BioNTech and Pfizer, and mRNA-1273 (SpikeVax), developed by Moderna, have been widely administered over the world. In phase III clinical trials, these vaccines have shown an efficacy of over 94% in preventing symptomatic infections caused by a prototype strain of the SARS-CoV-2. COVID-19 mRNA vaccines were the first globally approved mRNA vaccines. Both BNT162b2 and mRNA-1273 use gene encoding the prefusion-stabilized S-2P protein and employ lipid nanoparticles as the delivery system. Owing to the distinct characteristics of the different vaccine paltforms, there are variations in the vaccine-induced immune responses. To compare the characteristics of the immune response elicited by various COVID-19 vaccine platforms, we designed a head-to-head comparative study. We modified the RBD dimer immunogen used in the ZF2001 vaccine, to design a chimeric RBD dimer antigen composed of tandem RBDs from two different viral strains; which could induce a broader spectrum of immune responses. Using the Delta-Omicron RBD dimer as an immunogen, we selected vaccines from three platforms including recombinant protein subunit, adenovirus vector, and mRNA vaccines for a homologous and heterologous prime-boost immunization regimen in a head-to-head comparative study. We found that two doses of mRNA vaccine induced the highest antibody titers of specific IgG and neutralizing antibodies in mice, followed by the protein vaccine and AdC68 vaccine. The heterologous prime-boost studies showed that boosting with the mRNA vaccine as the second dose induced a stronger humoral immunity response, compared with protein subunit and AdC68 vaccines. In addition, the mRNA vaccine induced a strong CD4⁺ T cell responses, and the AdC68 vaccine induced a strong CD8⁺ T cell responses. In contrast, the protein subunit vaccine elicited a relatively weak cellular immune response. This study provides guidance for the next-generation of COVID-19 vaccine development and optimization of inoculation strategy in the real world.

Background. Three vaccines against SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) have now received emergency use authorization by the US Food and Drug Administration. Patients may have the opportunity to make a choice about which vaccine they prefer to receive. Vaccine hesitancy is a hurdle to the development of widespread immunity, with many patients struggling to decide whether to get vaccinated at all. Objective. Develop a decision model exploring the question, “Should I get vaccinated with mRNA or adenovirus vector vaccine (AVV) if either is available now?”Design. Markov state transition model with lifetime time horizon. Data Sources. MEDLINE searches, bibliographies from relevant English-language articles. Setting. United States, ambulatory clinical setting. Participants. Previously uninfected, nonimmunized adults in the United States. Interventions. 1) Do Not Vaccinate, 2) Vaccination with mRNA Vaccine, 3) Vaccination with Adenovirus Vector Vaccine. Main Measures. Quality-adjusted life years (QALYs). Key Results. Base case—for a healthy 65-year-old patient, both vaccines yield virtually equivalent results (difference of 0.0028 QALYs). In sensitivity analyses, receiving the AVV is preferred if the short-term morbidity associated with each vaccine dose exceeds 1.8 days. Both vaccines afford an even greater benefit compared with Do Not Vaccinate if the pandemic is in a surge phase with a rising incidence of infection or if the current 7-day incidence is greater than the base case estimate of 105 cases per 100,000. Conclusions. Preferred vaccination strategies change under differing assumptions, but differences in outcomes are negligible. The best advice for patients is to get vaccinated against COVID-19 disease with whatever vaccine is available first. Providing mRNA vaccine to the remaining eligible US population would result in an aggregate gain of 3.92 million QALYs.Highlights Question: Now that three vaccines have received emergency use authorization to prevent SARS-CoV-2, should I get vaccinated with either the mRNA (Moderna or Pfizer) or the adenovirus vector (Janssen/Johnson & Johnson) vaccine if either one is available now?Findings: In our base case, for a healthy 65-year-old patient, an mRNA vaccine is very slightly preferred over the adenovirus vector vaccine by 0.0028 QALYs, or slightly more than 1 day. However, both vaccines afford a substantial benefit compared with not getting vaccinated.Meaning: In conclusion, although different vaccine strategies are preferred under different modeling assumptions, in the final analysis the differences in outcomes are extremely small. Our best advice is to simply get vaccinated with whatever is available the soonest!

Background/Objectives: In previous studies, we demonstrated that the HIV-1 Env-Gag VLP mRNA vaccine elicited superior cellular immune responses. In this study, we further evaluated the immunogenicity of the Env-Gag VLP mRNA and adenovirus vector vaccines when administered individually or in combination in mice. Methods: BALB/c mice were divided into four groups and immunized twice at a 3-week interval. The three groups received either the Env-Gag VLP mRNA vaccine, the adenovirus vector vaccines expressing env and gag genes, or PBS as a control. The fourth group received a prime-boost regimen, primed with the Env-Gag mRNA vaccine and boosted with the adenovirus vector vaccines. The HIV-1 specific cellular and humoral immune responses were measured 1, 2, 4 and 8 weeks after the last immunization. Results/Conclusions: The results showed that the mRNA vaccines prime-adenovirus vector vaccines boost elicited higher cellular immune responses than those induced by homologous regimens at multiple time points, especially 8 weeks after the last immunization. Although the level of gp120 binding antibody in the combined immunization group is significantly lower than that of in the VLP mRNA vaccine group, a more balanced Th1/Th2 responses were induced in the combined immunization group, and significantly higher and longer-lasting neutralizing antibody levels were detected in this group making it a very promising HIV vaccine strategy.

mRNA and adenoviral vector vaccine platforms were used for the primary series of COVID-19 vaccines in many countries. However, the distinct immunogenic properties on these platforms remain less understood. We traced neutralizing antibodies, memory B cells, and T cells longitudinally in cohorts that received either mRNA (BNT162b2 or mRNA-1273) or adenoviral vector (ChAdOx1) vaccines with homologous or heterologous regimens (total 9 groups, n = 26–28 for each group) at 4 weeks interval. The priming and boosting effects on various immune parameters were comparably assessed between mRNA and adenoviral vector platforms. We found that initial priming by adenoviral vector vaccine elicited robust T cell responses, but B cell responses, including antibody titers, were relatively lower than those elicited by mRNA priming. The dissociation between T cell and antibody responses were exaggerated at greater extents after the homologous booster with the adenoviral vector vaccine, resulting in 5-19-fold lower antibody titers despite comparable spike-specific T cell numbers at day 28 after the boost. Robust IFN-γ and few IL-2 and IL-5 production characterized T cell functionality primed by adenoviral vector. Boosting with mRNA vaccines restored their IL-2 and IL-5 production at some extents, but the IL-5 T cell responses elicited by adenoviral vector/mRNA heterologous regimen waned faster than those by mRNA homologous regimen. Thus, our data revealed that the cytokine production of helper T cells was skewed by adenoviral vector priming, leading to the attenuated IL-2 and IL-5 responses which were prolonged even after mRNA boosting, suggesting an imprinting of T-cell functionality depending on the vaccine platform used for initial priming. These results highlight the importance of selecting vaccine platforms based on the immunogenic properties.

Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with Multiple Sclerosis

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce. To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU. This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021. COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine). The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders. Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P < .001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P < .001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P < .001), primarily male individuals (110 patients [79.1%] vs 252 patients [60.9%]; P < .001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P < .001) and had higher ratio of arterial partial pressure of oxygen (Pao2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients. In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people.

IntroductionSolid-organ transplant (SOT) recipients have an excess mortality risk from severe acute respiratory syndrome coronavirus (SARS-CoV-2), while simultaneously initial reports have suggested blunted responses to messenger RNA (mRNA) vaccination. A...

Two COVID-19 mRNA (of BNT162b2, mRNA-1273) and two adenovirus vector vaccines (ChAdOx1 and Janssen) are licensed in Europe, but optimization of regime and dosing is still ongoing. Here we show in health care workers (n = 328) that two doses of BNT162b2, mRNA-1273, or a combination of ChAdOx1 adenovirus vector and mRNA vaccines administrated with a long 12-week dose interval induce equally high levels of anti-SARS-CoV-2 spike antibodies and neutralizing antibodies against D614 and Delta variant. By contrast, two doses of BNT162b2 with a short 3-week interval induce 2-3-fold lower titers of neutralizing antibodies than those from the 12-week interval, yet a third BNT162b2 or mRNA-1273 booster dose increases the antibody levels 4-fold compared to the levels after the second dose, as well as induces neutralizing antibody against Omicron BA.1 variant. Our data thus indicates that a third COVID-19 mRNA vaccine may induce cross-protective neutralizing antibodies against multiple variants.

Should women undergoing in vitro fertilization treatment or who are in the first trimester of pregnancy be vaccinated immediately against COVID-19

Introduction: Many vaccines have been developed to alleviate the risk of infection against the pandemic corona virus disease 2019 (COVID-19). Tooth and palatal development are influenced by acquired or inherited variables that may affect the general health. The effect of vaccines on organ development is an essential step for vaccine safety insurance.Aim of the study: To detect the effect of different types of COVID-19 vaccines on tooth and palatal development..Materials and Methods: Sixty female rats were arranged into four groups. Each group received either intramuscular injection of saline (Group I), mRNA vaccine (Group II), adenoviral vector vaccine (Group III), or inactivated vaccine (Group IV) at 21 and 14 days before mating and on the ninth day of gestation. The heads of the offspring “one day old” were collected, processed and stained by hematoxylin and eosin (H&E), Beta-catenin (β-catenin) and transforming growth factor–Beta2 (TGF-β2). The expressions of β-catenin and TGF-β2 in the developing tooth germ and palate were analyzed statistically.Results: No histological or morphological changes in the developing teeth and palate were recorded in all studied groups except for the developing tooth germs in groups III and IV. All groups showed positive β-catenin and TGF-β2 immunoreactivity in the developing tooth germ and palate. Statistically, the vaccinated groups showed a significant difference in immunopositive area% to Group I, except β-catenin in Group II, and TGF-β2 of the developing palate in groups II and IV.Conclusion: mRNA COVID-19 vaccine is safer than adenoviral vector and inactivated vaccines regarding tooth or/and palatal development

To the Editor: To control the coronavirus disease 2019 (COVID-19) pandemic and reduce the complications and deaths resulting from the transmission of the disease, a variety of COVID-19 vaccines, such as mRNA vaccines, adenovirus-vector vaccines, inactivated viral vaccines, and others, have been licensed for emergency use. Most of these vaccines were rolled out in different countries following the successful completion of phase 3 clinical trials. Scale-up of vaccine production and vaccination have provided notable protection to large populations, although some vaccines may cause side effects. Furthermore, as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has mutated and spread further over time, some notable novel variants have emerged but whether these variants are vulnerable to currently available vaccines is yet to be determined. Despite the availability of vaccines across the world varies and some countries are still struggling to obtain vaccines and effectively store vaccines, a large proportion of people have now been vaccinated. An international consensus has been reached on the use of global mass vaccination to curb the epidemic. Remarkable achievements are demonstrated because the severity and mortality rate have decreased significantly compared with early 2020. Therefore, it is appropriate to evaluate and reassess the current epidemic situation and formulate timely plans to achieve herd immunity. To date, there have been 337 candidate COVID-19 vaccines that have been reported or registered worldwide [Supplementary Figure 1, https://links.lww.com/CM9/B390]. Of these, 142 are undergoing clinical development, while the rest of them are in preclinical trials. The protein subunit is the most commonly used platform, accounting for 33% of all vaccine candidates. Most current vaccines are on a two-dose schedule to achieve optimal immunity against SARS-CoV-2. Most candidates are administered by intramuscular injections. The mechanisms for how different vaccines act on the immune system are presented in Supplementary Figure 2, https://links.lww.com/CM9/B390. Based on the different production mechanisms, vaccines are mainly classified as inactivated vaccines, protein subunit vaccines, vector-based vaccines, mRNA-based vaccines and deoxyribonucleic acid (DNA) based vaccines, virus-like particle vaccines, and live-attenuated vaccines. According to World Health Organization (WHO), the vaccines procured the most are Comirnaty (Pfizer BioNTech, America-Germany), Spikevax (Moderna, America), Vaxzevria (AstraZeneca, Britain), Covishield (SII, India), and CoronaVac (Sinovac, China). The characteristics of the selected vaccines are listed and compared in Supplementary Table 1, https://links.lww.com/CM9/B390. Live-attenuated vaccines might possess a risk of viral infection and transmission. DNA vaccines in nucleic acid vaccines present the risk of oncogene activation, inactivation of tumor suppressor genes, accidental replications, or chromosomal instability due to the potential integration into the host genome. mRNA could bind to endosomal or the cytosol pattern recognition receptors before translation. Endosomal single-stranded or double-stranded ribonucleic acid (RNA) can be recognized by toll-like receptor 3, 7, and 8, while short and long filaments of double-stranded RNAs may be recognized by retinoic acid-inducible gene-I in the cytoplasm, as well as melanoma differentiation-associated protein 5. The subsequent activation of innate immunity can theoretically generate pro-inflammatory cascades, for instance, inflammasome formation and activation of the nuclear transcription factor-kappa B pathway.[1] This might lead to several potential adverse side effects or induce autoinflammatory or autoimmune conditions. Neutralizing antibodies generated from previous adenovirus infections might potentially prevent human cells from incorporating the adenovirus vector, or impact adenovirus vector vaccine safety by initiating an inappropriate immune response. Most adverse reactions occur during the window period after vaccination. Almost all anaphylactic reactions (injection site redness and swelling, fatigue, and fever) occurred within 15 to 30 min.[2] Therefore, 30 min is recommended as the observation period post-vaccination for those individuals at risk of allergic reactions. The incidence of adverse reactions from adenovirus and mRNA vaccines was higher than that of other vaccines. Severe adverse reactions were rarely seen in adults,[3] and the incidence rates of anaphylaxis and myocarditis were reported to be 2.5 to 4.8 billion and 6 to 27 billion for mRNA vaccines, respectively. Thrombosis with thrombocytopenia syndrome was reported as an adverse reaction for the AstraZeneca vaccine (2 billion), while for the Ad.26.COV2.S vaccine (Johnson & Johnson, USA), thrombosis with thrombocytopenia syndrome (3 million) and Guillain–Barré syndrome (7.8 million) were reported. Transverse myelitis (1 million) was reported for BNT162b2. Capillary leak syndrome and multisystem inflammatory syndrome were possible side reactions for AZD1222 (AstraZeneca, Britain). The major severe adverse reactions are summarized in Supplementary Table 1, https://links.lww.com/CM9/B390. SARS-CoV-2 vaccines have been developed in a relatively short time after the initial outbreak, using knowledge gained from SARS and Middle East respiratory syndrome vaccines. The Spike protein, a large transmembrane protein I that contains a receptor-binding domain (RBD), is a common antigen target in vaccine development. The RBD spike protein fragment, widely used in vaccine development, is considered highly antigenic and plays an important role in humoral and cellular immune responses. This protein also induces neutralizing antibodies that play an essential role in protective immunity by preventing host cell attachment and infection. Furthermore, when used in conjunction with S protein epitopes, conserved nucleocapsid (N) and membrane (M) proteins could synergically enhance immunogenicity, and T cell and cytokine release. At present, SARS-CoV-2 epitope vaccines based on polypeptide subunits include the adjuvant, cytotoxic T cells, helper T cells, and B-cell epitopes. Non-toxicity, non-sensitization, thermostability, and the capability to induce humoral and cell-mediated immunological reactions are advantages of these vaccines. The key to designing peptide vaccines is the recognition of B-cell and T-cell epitopes that are immunodominant for specific immune responses. Variants of the SARS-CoV-2 spike protein have been reported worldwide. The spike protein is highly glycosylated; therefore, new variants may have different infectivity and antigenicity. Newly emerging, fast-spreading variants of SARS-CoV-2 can also reduce the overall protective effects of vaccines. Based on the transmissibility, pathogenicity, and immunogenicity, significant variants are divided by the WHO into a "variant of concern (VOC)" and "variant of interest." There are currently five VOC mutants identified by the WHO: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). As there have been many reports on the previous variants, including alpha, beta, and gamma, we focus on the current primary strain with high transmissibility. Former data are summarized in Supplementary Table 2, https://links.lww.com/CM9/B390. With up to 37 amino acid mutations on its S protein, the spike protein of the Omicron mutant exhibits a stronger binding ability to angiotensin-converting enzyme 2, which explains the potential mechanism underpinning its enhanced infectivity. Moreover, Omicron is believed to be associated with a higher risk of reinfection and a significantly enhanced immune escape ability, although the underlying mechanism remains unclear. As reported, the neutralization of the Omicron variant was undetectable in most vaccines, which may result from its ominous antigenic properties. The emergence of the Omicron variant has raised concern over the efficacy of neutralizing antibodies induced by COVID-19 vaccines as many vaccinated individuals have been infected with Omicron. Two BioNTech vaccinations, which provide more than 90% protection against serious Delta variant infection, may be significantly less effective against Omicron. Neutralizing antibodies against omicron were detectable in only about 20% to 24% recipients of BNT162b2,[4] and undetectable in all Coronavac recipients. The geometric mean neutralization antibody titers (GMT) against the Omicron variant in BNT162b2 recipients were significantly lower compared with Beta and Delta variants. Laboratory investigations suggest that Pfizer-BioNTech vaccines appear to offer better protection from the Omicron with a third dose as a booster, the latter of which increase the neutralizing antibody titers by 25-fold compared with the other two doses. Notwithstanding the low efficiency of the current vaccines against the novel variant, vaccines seem to have the potential to reduce the severity and death rate in individuals infected with omicron. The results about effectiveness of a few vaccines on omicron published on scientific journals are summarized in Supplementary Table 3, https://links.lww.com/CM9/B390. Herd immunity refers to the interrupted transmission of the disease in a biological population that occurs when most individuals have developed immunity to pathogens. There are two main ways to achieve herd immunity: natural infection (passive immunity) or vaccination (active immunity). Current studies estimate that the basic reproduction number (R0) of COVID-19 is 2.5 to 5.8 in different studies,[5] which translates to a predicted herd immunity threshold of between 60% and 83%. In clinical trials, the vaccine efficacy has been reported to be between 60% and 95%, depending on the vaccine. These calculations indicate that higher vaccination coverage may be needed to interrupt transmission. Ultimately, with the global population approaching 8 billion, 11 billion doses, depending on the type of vaccine, may be needed to stop transmission. It seems that it is no longer reasonable to obtain herd immunity from natural infection, as individuals became reinfected even though the positive rate of serum antibody is high after the first infection. Previous infections cannot protect individuals from the epidemic due to the constant mutations of the virus. It was estimated that 250,000 might result from the policy of natural herd immunity. Thus, many countries that used to develop herd immunity by the natural infection have now resorted to the weapon of vaccines. In a previous study, among the residents who received at least one dose of vaccine, there were 822 novel coronavirus cases (4.5% of the vaccinated residents) from 0 to 14 days and 250 cases (1.4%) from 15 to 28 days. The infection rate of residents vaccinated with two doses of vaccine decreased from 1.0% to 0.3%, while the rate in unvaccinated residents also decreased from 4.3% to 0.3%.[6] Moreover, most infected patients are asymptomatic cases, indicating that the vaccine can not only reduce the infection rate among unvaccinated residents, but also reduce the severity of infected cases, which is consistent with the effect of vaccines on different variants. The WHO has declared that it supports achieving herd immunity through vaccination, rather than by allowing the disease to spread through any segment of the population. Given the fact that the GMT after vaccination usually becomes lower with the emergence of novel variants such as Omicron, whether vaccination is a long-term approach to developing herd immunity remains to be seen. Sufficiency and efficiency are challenges to developing herd immunity, which may lead to dilemmas in vaccination. Due to the emergence of the Delta variant and the lack of vaccines, the government of England has changed the schedule from providing authorized two doses to one that gives priority to the first dose, and postponed the second dose from 3–4 weeks to 12 weeks. It seems that under the condition of limited resources, a single dose will save more lives. Conversely, a single dose may lead to more vaccine failures or introduce mutations resistant to the vaccine, known as vaccine escape. Another dilemma is the priority of the vaccination afforded to different segments of the population. A study found that giving priority to vaccinating older people can reduce the number of deaths and hospitalizations and save the most lives. However, Indonesia focused on working age adults rather than the elderly to reduce community transmission faster, as adults of working age tend to be exposed to the environment. Besides, the intention of vaccination plays an important part in herd immunity, which depends on regions, the efficiency, type, and side effects of vaccines. According to an anonymous cross-sectional survey, people in Australia (96.4%), China (95.3%), and Norway (95.3%) are more likely to receive COVID-19 vaccines, while people in Japan (34.6%), the U.S. (29.4%), and Iran (27.9%) are unwilling to receive vaccinations. Males, elders, and people with lower education levels seem to be more resistant to vaccination. Vaccines with an efficiency of more than 90% and fewer adverse reactions are more popular, and mRNA-based vaccines are mostly unpopular in countries from the Southeast Asia. The efficiency and adverse reactions are issues of greatest concern, which may shed light on the direction to herd immunity.[7] In conclusion, vaccines are an important tool to curb the pandemic. Post-licensing studies need to be systematically conducted to investigate the core parameters of herd immunity, as well as the subsequent formulation of policies. COVID-19 vaccines have been developed and released within 11 months after the initial outbreak. In the near future, large-population vaccination and prevention measures still need to be implanted, which would ensure equitable global opportunities for vaccination and ensure immunity to emerging strains of the virus. Funding This study was supported by grants from the Logistic Support Department of Central Military Commission Health Care Project (No. 21BJZ35) and National Natural Science Foundation of Beijing (No. 7212104). Conflicts of interest None.

SummaryWe examined the possible non-specific effects of novel mRNA- and adenovirus-vector COVID-19 vaccines by reviewing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines. We calculated mortality risk ratios (RRs) for mRNA COVID-19 vaccines vs. placebo recipients and compared them with the RR for adenovirus-vector COVID-19 vaccine recipients vs. controls. The RR for overall mortality of mRNA vaccines vs. placebo was 1.03 (95% confidence interval [CI]: 0.63–1.71). In the adenovirus-vector vaccine RCTs, the RR for overall mortality was 0.37 (0.19–0.70). The two vaccine types differed significantly with respect to impact on overall mortality (p = 0.015). The RCTs of COVID-19 vaccines were unblinded rapidly, and controls were vaccinated. The results may therefore not be representative of the long-term effects. However, the data argue for performing RCTs of mRNA and adenovirus-vector vaccines head-to-head comparing long-term effects on overall mortality.

Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. The aim of this study was to validate whether immunogenicity differs for adenoviral vectored (AdV) versus mRNA vaccines against SARS-CoV-2, and to investigate how anti-vector immunity and B cell dynamics modulate immunogenicity. We enrolled SARS-CoV-2 infection-naïve health care workers who had received two doses of either AdV AZD1222 (n = 184) or mRNA BNT162b2 vaccine (n = 274) between April and October 2021. Blood was collected at least once, 10–48 days after vaccine dose 2 for antibody and B cell analyses. Median ages were 42 and 39 years, for AdV and mRNA vaccinees, respectively. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p < 0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine, which reflected greater B cell expansion and targeting of the RBD rather than an attenuating effect of anti-vector antibodies.ClinicalTrials.gov Identifier: NCT05110911.

Immunogenicity of a booster dose of a bivalent (Asp614Gly and omicron BA.4/5 variant) self-amplifying mRNA SARS-CoV-2 booster vaccine versus the BNT162b2 omicron BA.4/5 mRNA vaccine: a randomised phase 3 trial