Realising the potential of SARS-CoV-2 vaccines-a long shot?

The race to develop safe, effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced impressive results. As of Jan 18, 2021, 64 vaccines were in clinical development according to the WHO COVID-19 candidate vaccine database. Phase 3 data for two RNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), and the adenovirus-vectored vaccine ChAdOx1 nCoV-19 (Oxford University/AstraZeneca) have been published in peer-reviewed journals, and further phase 3 reports are expected imminently. Although the start of mass vaccination programmes should be celebrated, many challenges lie ahead in reaching eligible recipients and protecting those at risk from COVID-19-related morbidity and mortality.

The UK was quick off the mark: BNT162b2 was approved for use by the Medicines and Healthcare Products Regulatory Agency on Dec 2, 2020, followed by ChAdOx1 nCoV-19 and mRNA-1273, and more than 4 million people have received a first vaccine dose. But the UK's decision to give the second dose of BNT162b2 up to 12 weeks after the first—a delay introduced to allow more individuals to receive their first shot—has met with controversy, with Pfizer stressing that efficacy was tested with two doses given just 21 days apart. Delays in the delivery of BNT162b2 are currently affecting the UK and other European countries as Pfizer ramps up its production capacity, and limited supply of approved vaccines is likely to be an ongoing problem.

Other countries hit hard by COVID-19 have announced ambitious plans. On Jan 16, 2021, India launched its programme with the goal of reaching 300 million people by August, 2021. The country has approved the use of ChAdOx1 nCoV-19 and the whole-virion inactivated vaccine BBV152 (Bharat Biotech); however, there are fears that the rapid approval of BBV152, phase 3 results for which are not expected until March, 2021, might undermine confidence and add to the growing problem of vaccine hesitancy in India. India has huge vaccine-manufacturing capacity and both will be produced locally, but whether the challenges of reaching priority groups can be overcome remains to be seen. For many low-income and middle-income countries, the task ahead is formidable, with concerns about the availability and affordability of vaccines. International initiatives such as the COVID-19 Vaccines Global Access (COVAX) Facility aim to promote the equitable distribution of safe and efficacious vaccines.

Natural or vaccine-induced immunity has been a key focus of research since the start of the pandemic. Scientists worked quickly to describe the adaptive response to SARS-CoV-2 infection, including neutralising antibody and T-cell subsets. However, the duration of protection after infection is still uncertain and reinfection has been reported. The hope is that vaccines will provide lasting benefits, but careful monitoring will be needed to establish the durability of protection. Other priorities for research include the identification of immune correlates of asymptomatic or mild versus more severe disease, which could pave the way to new therapeutic approaches, and better mapping of protective epitopes to allow the fine-tuning of vaccine design and further development of therapeutic monoclonal antibodies. The long-term safety and efficacy of vaccines will need to be studied in diverse populations.

The ability of SARS-CoV-2 vaccines to prevent infection or ongoing transmission remains unclear. The impact of immunisation on hospital admissions will be an important focus as countries aim to keep health-care systems running and protect those most at risk of severe disease in the face of high levels of transmission. Emerging SARS-CoV-2 variants are a cause for concern. New variants include B.1.1.7, which recently emerged in the UK, B.1.351, and P.1. These lineages appear to be more transmissible than previous strains, although there is currently no evidence that they cause more severe disease or compromise the efficacy of available vaccines. Surveillance is needed to detect escape variants at an early stage. New variants also emphasise the ongoing need for public health mitigation strategies and add to the urgency of vaccine rollout across the globe.

Despite the promise of vaccination programmes and related research efforts, it will be months before the benefits start to be felt globally. In the meantime, a redoubling of efforts is needed to stem the transmission of COVID-19; to better understand the pathophysiology and clinical features of acute illness and the long-term consequences of SARS-CoV-2 infection; and to address the clinical needs of patients through evidence-based treatment and management strategies.

For the WHO COVID-19 candidate vaccine database see https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

For phase 3 data on the BNT162b2 vaccine see N Engl J Med 2020; 383: 2603–15

For phase 3 data on the mRNA-1273 vaccine see N Engl J Med 2020; published online Dec 30. https://doi.org/10.1056/NEJMoa2035389

For more on the COVAX Facility see https://www.gavi.org/covax-facility

For more on immunity after asymptomatic or mild SARS-CoV-2 infection see Sci Immunol 2020; published online Dec 23. https://doi.org/10.1126/sciimmunol.abf3698