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Under the shadow of the Covid-19 pandemic, global public health is facing unprecedented challenges. However, it is precisely in such a crisis that science and technology have demonstrated their enormous potential and power. Since the outbreak of the epidemic, the global scientific community and governments have closely cooperated to promote the rapid development and promotion of vaccines, achieving remarkable results. However, issues such as uneven distribution of vaccines and insufficient public willingness to receive vaccinations still plague the global fight against the pandemic.

Before the Covid-19 pandemic, the 1918 flu was the most severe infectious disease outbreak in US history, and the death toll caused by this Covid-19 pandemic was almost twice that of the 1918 flu. The Covid-19 pandemic has driven extraordinary progress in the field of vaccines, providing safe and effective vaccines for humanity and demonstrating the medical community’s ability to quickly respond to major challenges in the face of urgent public health needs. It is concerning that there is a fragile state in the national and global vaccine field, including issues related to vaccine distribution and administration. The third experience is that partnerships between private enterprises, governments, and academia are crucial for promoting the rapid development of the first generation Covid-19 vaccine. Based on these lessons learned, the Biomedical Advanced Research and Development Authority (BARDA) is seeking support for the development of a new generation of improved vaccines.

The NextGen project is a $5 billion initiative funded by the Department of Health and Human Services aimed at developing the next generation of healthcare solutions for Covid-19. This plan will support double-blind, active controlled Phase 2b trials to evaluate the safety, efficacy, and immunogenicity of experimental vaccines relative to approved vaccines in different ethnic and racial populations. We expect these vaccine platforms to be applicable to other infectious disease vaccines, enabling them to quickly respond to future health and safety threats. These experiments will involve multiple considerations.

The main endpoint of the proposed Phase 2b clinical trial is a vaccine efficacy improvement of over 30% over a 12-month observation period compared to already approved vaccines. Researchers will evaluate the efficacy of the new vaccine based on its protective effect against symptomatic Covid-19; In addition, as a secondary endpoint, participants will self test with nasal swabs on a weekly basis to obtain data on asymptomatic infections. The vaccines currently available in the United States are based on spike protein antigens and administered via intramuscular injection, while the next generation of candidate vaccines will rely on a more diverse platform, including spike protein genes and more conserved regions of the virus genome, such as genes encoding nucleocapsid, membrane, or other non structural proteins. The new platform may include recombinant viral vector vaccines that use vectors with/without the ability to replicate and contain genes encoding SARS-CoV-2 structural and non structural proteins. The second-generation self amplifying mRNA (samRNA) vaccine is a rapidly emerging technological form that can be evaluated as an alternative solution. The samRNA vaccine encodes replicases carrying selected immunogenic sequences into lipid nanoparticles to trigger precise adaptive immune responses. The potential advantages of this platform include lower RNA doses (which can reduce reactivity), longer lasting immune responses, and more stable vaccines at refrigerator temperatures.

The definition of correlation of protection (CoP) is a specific adaptive humoral and cellular immune response that can provide protection against infection or reinfection with specific pathogens. The Phase 2b trial will evaluate the potential CoPs of the Covid-19 vaccine. For many viruses, including coronaviruses, determining CoP has always been a challenge because multiple components of the immune response work together to inactivate the virus, including neutralizing and non neutralizing antibodies (such as agglutination antibodies, precipitation antibodies, or complement fixation antibodies), isotype antibodies, CD4+and CD8+T cells, antibody Fc effector function, and memory cells. More complexly, the role of these components in resisting SARS-CoV-2 may vary depending on the anatomical site (such as circulation, tissue, or respiratory mucosal surface) and the endpoint considered (such as asymptomatic infection, symptomatic infection, or severe illness).

Although identifying CoP remains challenging, the results of pre-approval vaccine trials can help quantify the relationship between circulating neutralizing antibody levels and vaccine efficacy. Identify several benefits of CoP. A comprehensive CoP may make immune bridging studies on new vaccine platforms faster and more cost-effective than large placebo-controlled trials, and help evaluate the vaccine protective ability of populations not included in vaccine efficacy trials, such as children. Determining CoP can also evaluate the duration of immunity after infection with new strains or vaccination against new strains, and help determine when booster shots are needed.

The first Omicron variant appeared in November 2021. Compared to the original strain, it has approximately 30 amino acids replaced (including 15 amino acids in the spike protein), and is therefore designated as a variant of concern. In the previous epidemic caused by multiple COVID-19 variants such as alpha, beta, delta and kappa, the neutralizing activity of antibodies produced by infection or vaccination against the Omikjon variant was reduced, which made Omikjon replace the delta virus globally within a few weeks. Although the replication ability of Omicron in lower respiratory cells has decreased compared to early strains, it initially led to a sharp increase in infection rates. The subsequent evolution of the Omicron variant gradually enhanced its ability to evade existing neutralizing antibodies, and its binding activity to angiotensin converting enzyme 2 (ACE2) receptors also increased, leading to an increase in transmission rate. However, the severe burden of these strains (including JN.1 offspring of BA.2.86) is relatively low. Non humoral immunity may be the reason for the lower severity of the disease compared to previous transmissions. The survival of Covid-19 patients who did not produce neutralizing antibodies (such as those with treatment induced B-cell deficiency) further highlights the importance of cellular immunity.

These observations indicate that antigen-specific memory T cells are less affected by spike protein escape mutations in mutant strains compared to antibodies. Memory T cells seem to be able to recognize highly conserved peptide epitopes on spike protein receptor binding domains and other viral encoded structural and non structural proteins. This discovery may explain why mutant strains with lower sensitivity to existing neutralizing antibodies may be associated with milder disease, and point out the necessity of improving the detection of T cell-mediated immune responses.

The upper respiratory tract is the first point of contact and entry for respiratory viruses such as coronaviruses (the nasal epithelium is rich in ACE2 receptors), where both innate and adaptive immune responses occur. The current available intramuscular vaccines have limited ability to induce strong mucosal immune responses. In populations with high vaccination rates, the continued prevalence of the variant strain can exert selective pressure on the variant strain, increasing the likelihood of immune escape. Mucosal vaccines can stimulate both local respiratory mucosal immune responses and systemic immune responses, limiting community transmission and making them an ideal vaccine. Other routes of vaccination include intradermal (microarray patch), oral (tablet), intranasal (spray or drop), or inhalation (aerosol). The emergence of needle free vaccines may reduce hesitation towards vaccines and increase their acceptance. Regardless of the approach taken, simplifying vaccination will reduce the burden on healthcare workers, thereby improving vaccine accessibility and facilitating future pandemic response measures, especially when it is necessary to implement large-scale vaccination programs. The efficacy of single dose booster vaccines using enteric coated, temperature stable vaccine tablets and intranasal vaccines will be evaluated by assessing antigen-specific IgA responses in the gastrointestinal and respiratory tracts.

In phase 2b clinical trials, careful monitoring of participant safety is equally important as improving vaccine efficacy. We will systematically collect and analyze security data. Although the safety of Covid-19 vaccines has been well proven, adverse reactions may occur after any vaccination. In the NextGen trial, approximately 10000 participants will undergo adverse reaction risk assessment and will be randomly assigned to receive either the trial vaccine or a licensed vaccine in a 1:1 ratio. A detailed assessment of local and systemic adverse reactions will provide important information, including the incidence of complications such as myocarditis or pericarditis.

A serious challenge faced by vaccine manufacturers is the need to maintain rapid response capabilities; Manufacturers must be able to produce hundreds of millions of doses of vaccines within 100 days of the outbreak, which is also a goal set by the government. As the pandemic weakens and the pandemic intermission approaches, vaccine demand will sharply decrease, and manufacturers will face challenges related to preserving supply chains, basic materials (enzymes, lipids, buffers, and nucleotides), and filling and processing capabilities. At present, the demand for Covid-19 vaccines in society is lower than the demand in 2021, but production processes that operate on a scale smaller than the “full-scale pandemic” still need to be validated by regulatory authorities. Further clinical development also requires validation from regulatory authorities, which may include inter batch consistency studies and subsequent Phase 3 efficacy plans. If the results of the planned Phase 2b trial are optimistic, it will greatly reduce the related risks of conducting Phase 3 trials and stimulate private investment in such trials, thus potentially achieving commercial development.

The duration of the current epidemic hiatus is still unknown, but recent experience suggests that this period should not be wasted. This period has provided us with an opportunity to expand people’s understanding of vaccine immunology and rebuild trust and confidence in vaccines for as many people as possible.