A dendritic cell-recruiting, antimicrobial blood clot hydrogel for melanoma recurrence prevention and infected wound management.

Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management.

Immune-modulative nano-gel-nano system for patient-favorable cancer therapy.

Current cancer immunotherapies exhibit low response rates attributed to suppressive tumor immune microenvironments (TIMEs). To address these unfavorable TIMEs, supplementation with tumor-associated antigens and stimulation of immune cells at target sites are indispensable for eliciting anti-tumoral immune responses. Previous research has explored the induction of immunotherapy through multiple injections and implants; however, these approaches lack consideration for patient convenience and the implementation of finely tunable immune response control systems to mitigate the side effects of over-inflammatory responses, such as cytokine storms. In this context, we describe a patient-centric nano-gel-nano system capable of sustained generation of tumor-associated antigens and release of adjuvants. This is achieved through the specific delivery of drugs to cancer cells and antigens/adjuvants to immune cells over the long term, maintaining proper concentrations within the tumor site with a single injection. This system demonstrates local immunity against tumors with a single injection, enhances the therapeutic efficacy of immune checkpoint blockades, and induces systemic and memory T cell responses, thus minimizing systemic side effects.

A heterogeneous continuous age-structured model of mumps with vaccine.

In classical mumps models, individuals are generally assumed to be uniformly mixed (homogeneous), ignoring population heterogeneity (preference, activity, etc.). Age is the key to catching mixed patterns in developing mathematical models for mumps. A continuous heterogeneous age-structured model for mumps with vaccines has been developed in this paper. The stability of age-structured models is a difficult question. An explicit formula of R 0 was defined for the various mixing modes (isolation, proportional and heterogeneous mixing) with or without the vaccine. The results show that the endemic steady state is unique and locally stable if R 0 > 1 without any additional conditions. A number of numerical examples are given to support the theory.

The immunological and pharmacokinetic evaluation of Lipid-PLGA hybrid nanoparticle-based oxycodone vaccines.

The current opioid epidemic is one of the most profound public health crises facing the United States. Despite that it has been under the spotlight for years, available treatments for opioid use disorder (OUD) and overdose are limited to opioid receptor ligands such as the agonist methadone and the overdose reversing drugs such as naloxone. Vaccines are emerging as an alternative strategy to combat OUD and prevent relapse and overdose. Most vaccine candidates consist of a conjugate structure containing the target opioid attached to an immunogenic carrier protein. However, conjugate vaccines have demonstrated some intrinsic shortfalls, such as fast degradation and poor recognition by immune cells. To overcome these challenges, we proposed a lipid-PLGA hybrid nanoparticle (hNP)-based vaccine against oxycodone (OXY), which is one of the most frequently misused opioid analgesics. The hNP-based OXY vaccine exhibited superior immunogenicity and pharmacokinetic efficacy in comparison to its conjugate vaccine counterpart. Specifically, the hNP-based OXY vaccine formulated with subunit keyhole limpet hemocyanin (sKLH) as the carrier protein and aluminum hydroxide (Alum) as the adjuvant (OXY-sKLH-hNP(Alum)) elicited the most potent OXY-specific antibody response in mice. The induced antibodies efficiently bound with OXY molecules in blood and suppressed their entry into the brain. In a following dose-response study, OXY-sKLH-hNP(Alum) equivalent to 60 µg of sKLH was determined to be the most promising OXY vaccine candidate moving forward. This study provides evidence that hybrid nanoparticle-based vaccines may be superior vaccine candidates than conjugate vaccines and will be beneficial in treating those suffering from OUD.

Use of the Abrysvo Vaccine in Pregnancy to Prevent Respiratory Syncytial Virus in Infants: A Review.

The FDA's approval of Pfizer's new respiratory syncytial virus (RSV) prefusion (preF) vaccine, Abrysvo, marks a critical milestone in infant health and well-being by preventing lower respiratory tract infections in the most vulnerable. The vaccine has been approved for administration to pregnant women at 32 to 36 weeks of gestation and elderly people over 60. This review explores the Abrysvo vaccine, detailing its mechanism, efficacy, safety, and adverse events. It aims to inform healthcare providers about this vital method for safeguarding infant respiratory health through maternal immunization.

Robust and persistent B-cell responses following SARS-CoV-2 vaccine determine protection from SARS-CoV-2 infection.

Introduction: A clear immune correlate of protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has not been defined. We explored antibody, B-cell, and T-cell responses to the third-dose vaccine and relationship to incident SARS-CoV-2 infection. Methods: Adults in a prospective cohort provided blood samples at day 0, day 14, and 10 months after the third-dose SARS-CoV-2 vaccine. Participants self-reported incident SARS-CoV-2 infection. Plasma anti-SARS-CoV-2 receptor-binding domain (RBD) and spike-subunit-1 and spike-subunit-2 antibodies were measured. A sub-study assessed SARS-CoV-2-specific plasma and memory B-cell and memory T-cell responses in peripheral blood mononuclear cells by enzyme-linked immunospot. Comparative analysis between participants who developed incident infection and uninfected participants utilised non-parametric t-tests, Kaplan-Meier survival analysis, and Cox proportional hazard ratios. Results: Of the 132 participants, 47 (36%) reported incident SARS-CoV-2 infection at a median 16.5 (16.25-21) weeks after the third-dose vaccination. RBD titres and B-cell responses, but not T-cell responses, increased after the third-dose vaccine. Whereas no significant difference in day 14 antibody titres or T-cell responses was observed between participants with and without incident SARS-CoV-2 infection, RBD memory B-cell frequencies were significantly higher in those who did not develop infection [10.0% (4.5%-16.0%) versus 4.9% (1.6%-9.3%), p = 0.01]. RBD titres and memory B-cell frequencies remained significantly higher at 10 months than day 0 levels (p < 0.01). Discussion: Robust antibody and B-cell responses persisted at 10 months following the third-dose vaccination. Higher memory B-cell frequencies, rather than antibody titres or T-cell responses, predicted protection from subsequent infection, identifying memory B cells as a correlate of protection.

Parental Attitudes and Hesitancy About COVID-19 Vaccination Versus Routine Childhood Vaccination in a Selected Hospital in the United Arab Emirates: A Cross-Sectional Study.

Background: A complex interplay of social and political influences, cultural and religious beliefs, the availability and interpretation of health and scientific information, individual and population experiences with health systems, and government policies contributes to the anxiety about vaccines and their programs that results in vaccine hesitancy. Vaccine hesitancy is becoming a serious threat to vaccination programs; in 2019, the World Health Organization (WHO) listed it as one of the top ten global health threats. The negative impacts of antivaccination movements are blamed for the major portion of the global resistance to vaccination. Objective: To evaluate and compare parental attitudes and reluctance regarding routine childhood vaccinations versus COVID-19 vaccines among children in the United Arab Emirates (UAE). Methods: A study of 102 parents with children admitted to SAQR Hospital in Ras Al Khaimah, UAE, was conducted using a convenience sample approach in a descriptive cross-sectional study. One-on-one interviews were conducted to gather data using the standardized Vaccine Hesitancy Scale (VHS) questionnaire developed by the WHO. Statistical Package for Social Sciences version 25 was used for data analysis. Results: Vaccine-hesitant respondents are also highly resistant to the required proof of vaccination. A statistically significant difference (P = .000) was observed between parental reluctance to receive the COVID-19 vaccination and routine childhood vaccination. Parental knowledge of the COVID-19 vaccine hesitancy (P = .001) and confidence (P = .000) showed a statistically significant correlation. No significant correlation was observed with sociodemographic factors. Conclusion: The impact of vaccine hesitancy on herd immunity, social, psychological, and public health strategies to combat vaccine hesitancy was observed in this study with various challenges to overcome in COVID-19 vaccination campaigns. Expanding access to and acceptance of vaccines among parents in low- and middle-income nations, as well as raising vaccination rates among those who express a lack of confidence in vaccines.

Behcet's disease-related panuveitis following COVID-19 vaccination: A case report.

BACKGROUND: Behcet's disease (BD) is an inflammatory disorder known for various symptoms, including oral and genital ulcers and ocular inflammation. Panuveitis, a severe eye condition, is rare as the first sign of BD. CASE SUMMARY: We present an unusual case of a 30-year-old man who developed panuveitis after receiving the mRNA-based coronavirus disease 2019 (COVID-19) vaccine (Moderna). Laboratory tests ruled out infections, but he had a positive HLA-B51 result and a history of genital ulcer and oral ulcers, leading to a BD diagnosis. Treatment with corticosteroids improved his condition. Interestingly, he had another episode of panuveitis after the second mRNA vaccine dose, which also responded to corticosteroids. CONCLUSION: This case highlights the rare onset of BD following mRNA COVID-19 vaccination, suggesting a potential link between these vaccines and BD's eye symptoms, emphasizing the importance of quick treatment in similar cases.

Therapeutic Vaccines and Nucleic Acid Drugs for Cardiovascular Disease.

To combat the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), novel vaccine modalities, such as messenger RNA vaccines, were rapidly developed and have shown high efficacy. This new vaccine technology, underpinned by intensive immunological analysis, is now being applied to the production of other vaccines. For over 10 years, we have been developing therapeutic vaccines for non-infectious diseases. The epitope vaccine approach, which combines a B-cell epitope with exogenous T-cell epitopes presented through major histocompatibility complex molecules, has been proposed to induce antibody production. This vaccine type is designed to efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. If therapeutic vaccines become established as treatment options for conditions such as hypertension or dyslipidemia, their administration-potentially only a few times per year-could replace the need for daily medication. Nucleic acid drugs, including small interfering RNA and antisense oligonucleotides, have recently received attention as long-term agonists, similar to vaccines. Therefore, therapeutic vaccines or nucleic acid drugs could represent a novel strategy for controlling the progression of cardiovascular diseases. It is hoped that the accumulation of immunological findings and advances in vaccine technology will provide valuable insights into the development of vaccines for treating cardiovascular diseases.

Chimeric Antigen-LgDNA Nanoparticles Attenuate Airway Th2 Polarization.

Introduction: The therapeutic efficacy for airway allergies needs to be improved. Th2 polarization is a primary pathological feature of airway allergies. We constructed chimeric antigen-LgDNA (Lactobacillus rhamnosus DNA) nanoparticles (CAP-NPs). The effects of CAP-NPs on reconciling airway Th2 polarization were tested. Methods: In this study, disulfide bond-linked antigen-major histocompatibility complex II (MHC II)-LgDNA nanoparticles (NPs) were constructed and designated CAP-NPs. An airway Th2 polarization mouse model was established to test the effects of CAP-NPs on suppressing the Th2 response. Results: The CAP-NP components of ovalbumin (OVA), major histocompatibility complex II (MHC II), and LgDNA were confirmed in a series of laboratory tests. The CAP-NPs remained stable at pH7.2 for at least 96 h. In in vitro experiments, CAP-NPs bound to the surface of OVA-specific CD4+ T cells, which resulted in apoptosis of the antigen-specific CD4+ T cells. Removal of any of the three components from the NPs abolished the induction of apoptosis of antigen specific CD4+ T cells. CAP-NPs increased the expression of lysine-specific demethylase 5A (KDM5A) in CD4+ T cells. Histone H3K9 and the gene promoter of caspase 8 were demethylated by KDM5A, which led to transcription and expression of the caspase 8 gene. Administration of CAP-NPs significantly alleviated experimental airway Th2 polarization through activating the caspase 8-apoptosis signaling pathway. Discussion: In this paper, we constructed CAP-NPs that could induce antigen-specific CD4+ T cell apoptosis. Administration of CAP-NPs efficiently alleviated experimental airway Th2 polarization.

[Refusal and hesitation regarding vaccination against COVID-19 in Douala, Cameroon]. / Refus et hésitation vis-à-vis de la vaccination anti-COVID-19 à Douala, Cameroun.

Introduction: vaccination is one of the strategies the World Health Organization recommends to reduce the burden of COVID-19. However, many African countries like Cameroon have low COVID-19 vaccination coverage. The purpose of this study was to investigate the reasons for the refusal of the population of the city of Douala to be vaccinated against COVID-19. Methods: we conducted a cross-sectional and analytical study in Douala from February 10 to May 31, 2022. Participants, aged at least 21 years and residing in the city of Douala, were interviewed. Associations between the variables of interest were measured using Chi-square and Fisher tests, with a 95% confidence interval. Results: a total of 1555 people were included in the study. Only 168 (11%) had been vaccinated. The proportion of vaccine refusal was high, with 711 (45.7%) refusing, 640 participants (41.1%) hesitating, and 204 people (13.2%) being in favor of COVID-19 vaccination. The main reasons for refusing anti-COVID-19 vaccination were fear of adverse effects (406; 44.8%), lack of information about vaccines (331; 36.5%), and lack of confidence (302; 33.3%). Factors associated with vaccine refusal were religion (p=0.026) and level of education (p=0.002). Conclusion: this study revealed low COVID-19 vaccination coverage in Douala, with a significant proportion of refusal and hesitation towards vaccination. Communication strategies should take into account the reasons and factors associated with refusal.

Acceptance of New Respiratory Syncytial Virus Vaccine among Pregnant Women in Nepal for Future Routine Immunization: A Descriptive Crosssectional Study.

INTRODUCTION: Children are at greatest risk for severe illness from Respiratory Syncytial Virus (RSV). The aim of the study was to find out the knowledge of RSV, practice and knowledge about vaccination during pregnancy and the willingness to accept vaccines against RSV during pregnancy in the future among mothers needs to be understood which would add up information for stakeholder and policy makers. METHODS: A preformed Performa was used for face-to-face interview was conducted among 340 pregnant women who visited the Antenatal clinic from 15-Oct-2023 to 30-Nov-2023 in their second and third trimester. Socio-demographic characteristics, knowledge and the attitude concerning antenatal vaccination affecting the acceptance of RSV vaccine were evaluated from the interview. RESULTS: The mean age was 28.4 years, with 310 (91.18%) already having at least one child. Six (1.76%) participants had previously heard about RSV, and 325 (95.59%) were aware of the problem caused by RSV after they were briefly explained about it in their local language. A total of 246 (72.35%) of the mothers expressed willingness to be vaccinated themselves rather than vaccinating their children if such an option existed. Only 2 (0.59%) participants were familiar with nasal vaccines, and only 18 (5.29%) believed in such vaccines being effective. Despite this, almost all participants 339 (99.71%) in the study demonstrated willingness to receive additional antenatal vaccines if approved for use in future. CONCLUSIONS: The study showed a limited understanding of RSV in children among pregnant women in Nepal. However, they are aware of the impact of bronchiolitis and expressed a strong willingness to undergo maternal vaccination against RSV.

Evaluation of Tembusu virus single-round infectious particle as vaccine vector in chickens.

Orthoflaviviruses are single-stranded RNA viruses characterized by highly efficient self-amplification of RNA in host cells, which makes them attractive vehicles for vaccines. Numerous preclinical and clinical studies have demonstrated the efficacy and safety of orthoflavivirus replicon vectors for vaccine development. In this study, we constructed Tembusu virus (TMUV) replicon-based single-round infectious particles (SRIPs) as vaccine development platform. To evaluate the potential of TMUV SRIPs as vaccines, we generated SRIPs that express the heterologous Fowl adenovirus 4 (FAdV-4) fiber2 protein and fiber2 head domain, named TMUVRP-fiber2 and TMUVRP-fiber2H, respectively. To assess the immunogenicity of the TMUV SRIPs, SPF chicks were intramuscularly inoculated twice. Our results showed that the TMUVRP-fiber2 vaccines elicited high levels of neutralizing antibodies. Challenge experiments showed that TMUVRP-fiber2 provided full protection against virulent FAdV-4 and significantly reduced viral shedding. Moreover, the immunogenicity of TMUVRP-fiber2H was significantly lower than that of TMUVRP-fiber2, which was reflected in the neutralizing antibody titer, survival rate, and virus shedding after challenge. Therefore, our results suggested that TMUV SRIPs are a promising novel platform for the development of vaccines for existing and emerging poultry diseases.

Wide circulation of type 1 vaccine-derived poliovirus strains in clinical specimens from suspected cases of poliomyelitis, their contacts and in wastewater in Madagascar since late 2020.

Madagascar has faced three major outbreaks of vaccine-derived polioviruses (VDPVs) in recent decades, with VDPV type 1 reemerging in late 2020. Here, we report the molecular characterization of these cVDPV1 strains. WHO protocols were used for poliovirus detection in stool and wastewater samples. Molecular genotyping was based on the 5' non-coding (5'NC), VP1, and 3Dpol regions. From 2020 to 2022, 92 of 5690 stool samples and 129 of 1046 wastewater samples tested positive for cVDPV1. Genetic analysis of the VP1 gene revealed 1.3%-6.1% variability compared to the Sabin strain. Most sequences showed mutations at neurovirulence attenuation sites. Phylogenetic analysis distributed strains into four genogroups originating from Southern Madagascar. All analyzed cVDPV1 strains were recombinant, containing mutated oral polio vaccine sequences in VP1 and type C enterovirus sequences in other regions. This study demonstrated that all strains were closely related during this epidemic.

Roles and responsibilities of participants, researchers, and the media in the communication of vaccine trials: Experience from the United Kingdom's first COVID-19 vaccine trial.

BACKGROUND: The media have played an important part in presenting arguments for and against vaccination. The potential for the media to influence public attitudes to vaccines is becoming increasingly crucial to address. METHODS: To understand the differing roles and responsibilities in the communication of vaccine trials we draw insight from a retrospective study of 349 survey responses and 102 semi-structured interviews conducted in 2020 with participants in the United Kingdom's first-in-human clinical trial of the Oxford-AstraZeneca COVID-19 vaccine. RESULTS: We found that trial participants had mixed views as to whether their participation conferred responsibility to communicate more widely about their trial experiences. Some participants perceived themselves to have an altruistic obligation to communicate to the media about the trial, and others felt that those who did share their participation had 'attention-seeking' motives. When participants did speak out they preferred to do so anonymously. Frustration was also reported with sensationalised and false media stories. Social media was viewed as a means to accelerate misinformation or as a force for recruitment and public education about trials. Participants were pleased to see trial investigators and trial team playing prominent roles in the media and this instilled confidence in the vaccine and the trial. We discuss these evolving roles and responsibilities for trial communication, concentrating on the views of participants about experiences, opportunities, and risks. CONCLUSIONS: We argue that the pandemic has demonstrated the need for clinical trials to be made more transparent as a scientific practice that requires better public understanding and engagement. For high-profile vaccine trials we recommend; (1) explicit and comprehensive guidance aimed at all participants for interactions with the media; (2) prioritising having open and effectively expressed accounts of trial composition, processes, and participation; (3) offering support and a direct communication channel for journalists to report trials by utilising internal press officers to engage with journalists.

Raising the case of hepatitis E: Report from the 2nd international HEV symposium.

The 2nd International Hepatitis E Virus Symposium was held on April 28 and 29, 2023, in London, UK. The conference was hosted by the International Vaccine Institute and brought together key clinicians, researchers, and private and public stakeholders for a dedicated forum on hepatitis E virus (HEV). The scientific program spanned multiple facets of HEV, from updates on clinical research and diagnostic advances to vaccine development. The conference highlighted presentations on several critical HEV vaccine studies that will greatly impact the field, including the largest effectiveness study of Hecolin vaccine outside of China and the first reactive mass-vaccination campaign in South Sudan. This report summarizes information shared at the convening and offers perspectives on the steps forward for hepatitis E.

Effect of a campaign with oral polio vaccine on general health: A cluster-randomised trial in rural Guinea-Bissau.

OBJECTIVES: To investigate in a cluster-randomised trial whether a campaign with oral polio vaccine (C-OPV) reduced mortality and morbidity. METHODS: We randomised 222 village clusters under demographic surveillance to an intervention (health check and C-OPV) or control group (health check only). Children aged 0-8 months were eligible. In Cox proportional hazards models with age as the underlying timescale, we compared rates of non-accidental mortality/hospital admission (composite primary outcome) during 12 months of follow-up. Secondary analyses considered non-accidental admission and mortality as separate outcomes. Potential effect modifiers identified in prior studies including sex, season, and timing of the first routine OPV dose (OPV0, scheduled at birth) were assessed. RESULTS: Among 10,175 children (5,288 in 111 intervention clusters/4,887 in 111 control clusters), we observed 265 deaths/admissions during 7,616 person-years at risk (intervention: 129; control: 136). C-OPV did not reduce the composite endpoint, hazard ratio (HR): 0.87, 95%CI: 0.68-1.12 or its separate components. C-OPV reduced the risk in children receiving OPV0<15 days of birth (HR=0.66, 95%CI: 0.46-0.95), but not in other children (p for interaction: 0.03). Interactions for other potential effect modifiers were not statistically significant. CONCLUSIONS: C-OPV had no overall effect on mortality/admissions, but the effect differed by early priming with OPV0.

Immunogenicity and immune persistence of Zagreb 2-1-1 regimen of rabies vaccine in Chinese healthy individuals: A randomized, parallel-controlled of homologous vaccine with different immune procedure study.

This study was a randomized, parallel-controlled of homologous vaccines with different immune procedure research to evaluate the immunogenicity and immune persistence of Zagreb 2-1-1 regimen of rabies vaccine in Chinese healthy individuals. 240 subjects aged ≤ 20、21-50、≥51 y were randomly divided into 2 groups (1:1), Zagreb 2-1-1 regimen receivers as experimental group and Essen 5 regimen receivers as controlled group. Researchers collected venous blood of each subject before vaccine injection and on the day 7, 14, 42, 180, 365 after first dose. The immunogenicity and immune persistence was assessed by neutralizing antibody. The positive rate of neutralizing antibody in experimental group was 14.53% on the 7th day, and raised to 100% on the 14th day. It showed no significant difference between experimental and controlled group (P>0.05). Either in experimental or controlled group, GMC of neutralizing antibody was up to the peak on the 14th day, and it showed no significant difference between two groups (P>0.05). On the 42nd day, the antibody positive rate remained 100% with both Zagreb 2-1-1 and Essen 5 regimens, and the GMC of antibodies also remained high level. Then, on the 180th and 365th day with both regimens, the GMC of antibodies dropped dramatically, although it remained above the protective level of 0.5 IU/ml, the positive rates dropped to 84.40% and 84.11% (on the 180th day), and 61.29% and 58.62% (on the 365th day). Rabies vaccine injected by Zagreb 2-1-1 regimen can produce neutralizing antibody fastly and perdurably.Registration: ClinicalTrials.gov #NCT01821911and NCT01827917.

Neurological Events Following COVID-19 Vaccination: Does Ethnicity Matter?

We conducted a retrospective cohort study in Ontario, Canada between December 1, 2020 and June 31, 2021 to compare the incidence of neurological events (hospitalization or emergency room visit) within six weeks of COVID-19 vaccination in Chinese, South Asian and Other ethnic groups. Compared to Others, the crude rates after the first dose for Bell's palsy, ischemic stroke and intracerebral hemorrhage were lower in Chinese (34, 159 and 48 per 1,000,000 doses) and in South Asians (44, 148 and 32), but similar after adjusting for age, sex and vaccine type. Our findings should help encourage vaccination for all, irrespective of ethnicity.

Invited Commentary: Thirty-five Years of Leaky Vaccines.

Over the past 35 years, the term "leaky vaccine" has gained widespread use in both mathematical modeling and epidemiologic methods for evaluating vaccines. Here we present a short history as we recall it of how the term was coined in the context of the history of sporozoite malaria vaccines that were thought to be possibly leaky in the 1980s. We draw a contrast with the all-or-none vaccine mechanism and review a few consequences for study design and population level effects. We invite readers to contribute information covering the time period preceding our memories in the 1980s as we may have overlooked something.