SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies.

Neither vaccination nor natural infection result in long-lasting protection against SARS-COV-2 infection and transmission, but both reduce the risk of severe COVID-19. To generate insights into optimal vaccination strategies for prevention of severe COVID-19 in the population, we extended a Susceptible-Exposed-Infectious-Removed (SEIR) mathematical model to compare the impact of vaccines that are highly protective against severe COVID-19 but not against infection and transmission, with those that block SARS-CoV-2 infection. Our analysis shows that vaccination strategies focusing on the prevention of severe COVID-19 are more effective than those focusing on creating of herd immunity. Key uncertainties that would affect the choice of vaccination strategies are: (1) the duration of protection against severe disease, (2) the protection against severe disease from variants that escape vaccine-induced immunity, (3) the incidence of long-COVID and level of protection provided by the vaccine, and (4) the rate of serious adverse events following vaccination, stratified by demographic variables.

Exploring the Role of Antiviral Nasal Sprays in the Control of Emerging Respiratory Infections in the Community.

INTRODUCTION: The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission. We explore the benefits and challenges of the use of antibody-based nasal sprays prior and post exposure to the virus. METHODS: The classic susceptible-exposed-infectious-removed (SEIR) mathematical model was extended to describe the potential population-level impact of intranasal antibody prophylaxis on controlling the spread of an emerging respiratory infection in the community. RESULTS: Intranasal administration of monoclonal antibodies provides only a short-term protection to the mucosal surface. Consequently, sustained intranasal antibody prophylaxis of a substantial proportion of the population would be needed to contain infections. Post-exposure prophylaxis against the development of severe disease would be essential for the overall reduction in hospital admissions. CONCLUSION: Antibody-based nasal sprays could provide protection against infection to individuals that are likely to be exposed to the virus. Large-scale administration for a long period of time would be challenging. Intranasal antibody prophylaxis alone cannot prevent community-wide transmission of the virus. It could be used along with other protective measures, such as non-pharmaceutical interventions, to bridge the time required to develop and produce effective vaccines, and complement active immunisation strategies.

Immune age and biological age as determinants of vaccine responsiveness among elderly populations: the Human Immunomics Initiative research program.

The Human Immunomics Initiative (HII), a joint project between the Harvard T.H. Chan School of Public Health and the Human Vaccines Project (HVP), focuses on studying immunity and the predictability of immuneresponsiveness to vaccines in aging populations. This paper describes the hypotheses and methodological approaches of this new collaborative initiative. Central to our thinking is the idea that predictors of age-related non-communicable diseases are the same as predictors for infectious diseases like COVID-19 and influenza. Fundamental to our approach is to differentiate between chronological, biological and immune age, and to use existing large-scale population cohorts. The latter provide well-typed phenotypic data on individuals' health status over time, readouts of routine clinical biochemical biomarkers to determine biological age, and bio-banked plasma samples to deep phenotype humoral immune responses as biomarkers of immune age. The first phase of the program involves 1. the exploration of biological age, humoral biomarkers of immune age, and genetics in a large multigenerational cohort, and 2. the subsequent development of models of immunity in relation to health status in a second, prospective cohort of an aging population. In the second phase, vaccine responses and efficacy of licensed COVID-19 vaccines in the presence and absence of influenza-, pneumococcal- and pertussis vaccines routinely offered to elderly, will be studied in older aged participants of prospective population-based cohorts in different geographical locations who will be selected for representing distinct biological and immune ages. The HII research program is aimed at relating vaccine responsiveness to biological and immune age, and identifying aging-related pathways crucial to enhance vaccine effectiveness in aging populations.

Development and deployment of COVID-19 vaccines for those most vulnerable.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.

External validity of phase III trials on vaccines against SARS-CoV-2 to a middle-aged and elderly Western European population.

Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51-106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to 'acute' or 'unstable preexisting' diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or 'unstable preexisting' diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11-97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5-96%. Importantly, considering persons ineligible due to 'acute' or 'unstable pre-existing' disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons.

Dissecting strategies to tune the therapeutic potential of SARS-CoV-2-specific monoclonal antibody CR3022.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross-SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.