COVID-19 Vaccine Development, Where Are We?

This is neatly discussed by Nelson Lean and Allison McGeer in a comment article in The Lancet dated May 28, 2020.

Clearly, developing a safe and effective COVID-19 vaccine is a global priority.

Researchers in China, Feng-Cai, Zhu and colleagues report about the safety, tolerability and immunogenicity of an adenovirus vectored COVID-19 vaccine undergoing a phase 1 trial and published in The Lancet. 

This vaccine expresses the full length spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2.

In the study, 108 healthy adults who had not been exposed to COVID-19 and aged between 18 and 60 were administered low, middle or high dose vaccine intramuscularly and observed for 28 days. 

At 14 days these individuals were found to have neutralising antibodies which were detectable with live virus or pseudovirus neutralisation studies.  They also were found to have binding antibodies to the receptor binding domain, the spike glycoprotein as measured by ELISA.  It was found that at 28 days the dose dependent antibody response peaked with seroconversion greater than a four-fold increase in neutralising antibody titre found in 50 to 75% of the participants in the middle and high dose groups.  Further studies showed a specific T-cell response toward the spike glycoprotein and a dose dependant response was detectable from 14 days in 83 to 97% of participants.

The most common reported side effect was fever in 50 cases, 46%, fatigue in 47, that is 44% of cases, headache in 42 cases, 39%, and muscle pain in 18, that is 17%.  These side effects were generally mild to moderate in severity but were more frequent in the high dose group. 

It was found that a high pre-existing Ad5 neutralising antibody titre compromised seroconversion and attenuated a peak T-cell response, although in this group vector-related febrile reactions were less frequent.  Older participants in the 45 to 60-year-old age group were found to have a significantly lower humoral response. 

This is one of the first in-human trials of a COVID-19 vaccine which showed immunogenicity. 

The multimillion dollar question here is whether responses are sustained over time and whether they can correlate with clinical protection after exposure to

Data from primate models suggests that the measurable neutralising antibodies and specific T-cell responses may be associated with protection against a virus challenge in vaccination or reinfection studies.  Unfortunately, further research is still necessary to evaluate the safety, clinical efficacy and duration of protection. 

A phase 2 study of this experimental vaccine using the middle or the lower dose has already begun in China and Canada has approved an early phase human trial. 

Other vaccine candidates are in rapid development and they are mostly based on the spike glycoprotein or its receptor binding domain because of its better immunogenic and protective potential.  They, however, use different antigen delivery platforms and several of these are entering phase 1 clinical trials or we are awaiting results.

Going forward, it is essential that future trials establish efficacy within defined target groups such as healthcare workers and individuals at high risk of severe disease. 

Clinical endpoints need to be defined, such as reduction in virus confirmed clinical illness, hospitalisations, deaths and the optimal duration of observation, e.g. virus exposure, side-effects and antibody titre changes. 

The results from this study show that some host factors might affect the vaccine response.  For example, suboptimal immunogenicity was found in the older patients.  This is comparable with the picture with influenza vaccine where the older age group have an adjuvant added. 

It would also appear that pre-existing immunity against the Ad5 vector could compromise immunogenicity and this may limit effectiveness in populations where the virus is endemic.  This is similar to the reported high seroprevalence around 30 to 80% found in vector-based vaccine development for other vaccines such as Ebola virus and HIV. 

It is unknown whether using rarer serotype or non-human primate adenovirus, adjuvants, booster or higher dose regimes, or other delivery platforms would achieve a greater degree of immunogenicity. 

There is also a concern that the vaccine causes antibody-dependent enhancement by promoting non-neutralising antibodies and an increased cellular immunopathology in those individuals who have been vaccinated if they are then infected by the SARS-CoV-2 virus.  This was suggested in preclinical studies of SARS-CoV-1 and Middle East respiratory syndrome coronavirus with whole-length spike glycoprotein.  This led to research on a receptor binding domain-focused vaccine. 

This is a complex subject and animal studies need to be considered to assess the potential risk of the SARS-CoV-2 vaccine candidate.  Pre-existing, non-spike-specific T-cell responses from endemic human coronavirus exposure, which cross-react with the SARS-CoV-2 virus, could further add to the difficulty in predicting vaccine response and safety.

All of these concerns need to be addressed in future clinical studies with close monitoring and regulatory review. However, amid all this uncertainty, the report of an immunogenic, tolerable vaccine candidate is encouraging and may be the starting line for COVID-19 vaccine development.

The London General Practice and London Global Practice is excited that vaccine development is entering phase 2 trials and looks forward to the development of a safe and efficacious vaccine.

The London General Practice

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