By Charles Nicolson

Countermeasures against Covid-19 including development, manufacture and provision of an effective vaccine.

This is the first of two final articles on the subject of the unforeseen emergence and rapid global spread of the novel coronavirus SARS-CoV-2, which has created a daunting global public health challenge.

To address this challenge NIAID – the National Institute of Allergy and Infectious Diseases in the USA – has been focusing its considerable resources of experience and expertise on infectious diseases for development of specific medical countermeasures including diagnostics, therapeutics, and vaccines.

The NIAID plan notes that a comprehensive strategy requires a coordinated effort by governmental, academic, private, and community-based organisations. The NIAID COVID-19 Research initiative defines the areas of Covid-19 research within NIAID capabilities and outlines the institute’s research priorities and goals.

This strategic plan builds on many other national efforts and represents a commitment from multiple US government agencies to improve coordination of national and international Covid-19 research and discovery efforts as well as the development of specialised countermeasures. NIAID actively participates in many other Covid-19 task forces to identify opportunities, ensure open communications, encourage resource sharing, and avoid duplication of efforts.

The NIAID plan is structured around four strategic research priorities:

Improving knowledge of SARS-CoV-2 and Covid-19, including studies to characterise the virus; how it is transmitted and to understand the natural history, epidemiology, host immunity, and the genetic, immunologic, and clinical associations leading to severe disease outcomes. This also includes expanding and accelerating the development of small and large animal models that replicate human disease.

Supporting the development of diagnostics and assays, including point-of-care molecular and antigen-based diagnostics for identifying and isolating Covid-19 cases and serological assays to better understand disease prevalence in the population. Diagnostics also will be essential when evaluating the effectiveness of proposed countermeasures.

Characterising and testing therapeutics, including identifying and evaluating re-purposed drugs along with novel broad-spectrum antiviral drugs, virus-targeted antibody-based therapies which include plasma-derived intravenous immunoglobulin (IVIG) and monoclonal antibodies within host-directed strategies to combat Covid-19.

Developing safe and effective vaccines against SARS-CoV-2, including support of clinical trial testing.

The resulting discoveries will not only help mitigate the current pandemic, but also be of value for prevention, diagnosis, and treatment of future emerging infectious diseases.

Developing a safe and effective SARS-CoV-2 vaccine is a priority for preventing, or at least reducing future outbreaks of the virus. Taking into account that vaccine candidates for MERS-CoV, SARS-CoV-1 and other coronaviruses have previously been developed, NIAID investigators in conjunction with the world-wide scientific community are well placed to use similar approaches in the current pandemic.

NIAID will utilise its broad intramural and extramural facilities to advance vaccine candidates through phase-1 safety and dosing clinical trials. Product candidates which show the most promising results will then be advanced to Phase-2/2b clinical trials.

Given the urgency of the response effort to develop a safe and effective vaccine, NIAID is prioritising promising vaccine candidates that can be rapidly produced and tested. NIAID, in collaboration with the biotechnology company Moderna, is conducting a Phase-1 clinical trial of a vaccine candidate that uses a messenger RNA (mRNA) vaccine platform expressing a NIAID-designed recombinant spike protein of SARS-CoV-2.

The trial is being conducted at various NIAID-funded clinical research sites. In one of these sites the first enrolled individual already began receiving vaccine treatment on March 16, 2020.

Preparations for a pivotal Phase 2/2b clinical trial of candidate mRNA-1273 are already under way. It is also imperative that preparations for the likelihood of any seasonal recurrences of SARS-CoV-2 are completed as soon as practically possible.

Given the theoretical risk of vaccine-enhanced respiratory diseases, large scale phase-2 trials are unlikely to be launched until these possibilities have been evaluated in animal models. Planning for those animal studies is already advanced, and, assuming favourable results, an initial phase-2/2b study would be launched late in 2020.

This represents a historically fast timeline for the development and testing of a vaccine candidate. Additionally, these studies will provide increasing amounts of information on immunity that will help accelerate the advancement of other vaccine candidates. If the mRNA-1273 vaccine candidate shows protection against SARS-CoV-2 infection in a phase-2/2b trial, NIAID will work with government partners to ensure that the vaccine is manufactured in sufficient quantities to allow prompt distribution to those at highest risk of acquiring Covid infections.

Although promising vaccine candidates may show efficacy in pre-clinical studies, many do not translate into effective vaccines in clinical trials. Therefore, it is crucial to support multiple promising pre-clinical vaccine candidates in the research and development pipeline. To that end, NIAID is advancing multiple additional SARS-CoV-2 vaccine candidates through its Rocky Mountain Laboratories (RML), including approaches that have shown promise against coronaviruses that cause SARS and MERS.

In addition, building on previous research to develop a MERS-CoV vaccine, scientists at RML are collaborating with Oxford University investigators to develop a SARS-CoV-2 vaccine that uses a chimpanzee adenovirus vector. RML investigators also are partnering with the biopharmaceutical company CureVac on an mRNA vaccine candidate and collaborating with the University of Washington on development of a universal coronavirus vaccine.

By leveraging its extensive expertise and research infrastructure, NIAID will continue working with partners and collaborators to advance promising SARS-CoV-2 vaccine candidates.

Building on past research on emerging pathogens, especially MERS-CoV and SARS-CoV-1, the virus that causes SARS, NIAID is using previously developed vaccine platforms to accelerate assessments regarding the potentials of SARS-CoV-2 vaccine candidates. This approach has already resulted in several promising strategies that may be leveraged for SARS-CoV-2, including vaccination using recombinant spike protein, chimpanzee adenovirus vaccine vector, virus-like particles, and live attenuated virus. In addition, NIAID is funding the development of novel vaccine candidates that will be effective across the lifespan of people from early childhood to elderly.

Regarding critical reagents to support vaccine development, appropriate tools are needed to identify the most promising vaccine candidates and to advance the development of lead candidates as rapidly as possible. To accelerate the vaccine pipeline, NIAID is generating master and working SARS-CoV-2 virus stocks and other reagents critical for developing SARS-CoV-2 immune assays, developing quantitative tests for characterising SARS-CoV2 assay material, developing a quantitative SARS-CoV-2-specific analysis, developing virus-specific neutralisation assays and developing quantitative assays for assessing SARS-CoV-2 viral loads.

Adjuvants – a new word to the writer and probably new to many readers of RACA Journal – are vaccine components that enable vaccines to provide protective immunity for longer periods. Selection of appropriate adjuvants is therefore important for developing safe and reliable vaccines.

NIAID is working with multiple collaborators to provide adjuvants to the research community for use in SARS-CoV-2 vaccine candidates. These adjuvants are at various stages of development and include compounds that specifically improve vaccine efficacy in elderly individuals or modulate host immunity toward protective responses while limiting or preventing undesirable or harmful inflammatory responses.


Developing effective medical and public health countermeasures against a newly emergent virus like SARS-CoV-2 requires a better understanding of the complex molecular and immune mechanisms involved in infection and disease. Studies that delineate the viral lifecycle and host immune responses to infection can lead to the identification of novel methods against SARS-CoV-2 infection and Covid-19. Early studies suggest that clinical manifestations of Covid-19 can vary significantly and disease severity can range from mild to critical.

Thus, a detailed understanding of the clinical course of the diseases are needed. Gaps also exist in our understanding of the dynamics of disease transmission in different populations over time, including the roles of paediatric and elderly populations in viral spreading.

Our current understanding of Covid-19 transmission is limited. While recent studies have suggested timeframes for virus survival in aerosols and on surfaces, the contributions of different routes of transmission and the dynamics of animal-to-human and human-to-human transmission remain unclear.

The diverse clinical types of Covid-19 having a high prevalence of asymptomatic cases add further complexity to understanding transmission dynamics. Providing a clearer picture of the natural history of viral shedding is a priority, both in acute cases and in asymptomatic infection.

There are delays in diagnosing some asymptomatic individuals because they do not come forward for treatment. In addition, determining the role they play in transmission would provide valuable insights. Elucidating the role of paediatric cases in the spread of SARS-CoV-2 is particularly important. Although paediatric Covid-19 cases are generally asymptomatic or have less severe symptoms than those of adults, the role that children play in spreading the virus is unknown.

Additionally, studies to identify potential animal reservoirs and better understand transmission from animals to humans are a research priority, as these reservoirs may lead to future virus introductions and re-emergence of disease in humans. Virus transmission depends on a complex interplay of host, viral, and environmental factors that contribute to disease incidence and spread.

Identifying the factors that maintain the disease transmission cycle is critical to developing effective medical countermeasures and public health interventions that will prevent future pandemics.


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