Practice Resources

Adverse events following immunization (AEFI) are obviously a concern for all new vaccines. Surveillance for vaccine safety signals  and AEFI are critical for the evaluation of vaccine safety.   “Vaccine safety signals typically arise when unexpected events are reported in clinical trials or passive or active surveillance systems or special studies establish temporal relationship between vaccine(s) and AEFI without establishing a causal relationship (true vaccine adverse reaction).”¹  On investigation, safety signals may ultimately be confirmed as true vaccine reactions or spurious signals.   Safety is assessed in all FDA phases of vaccine development, including pre-clinical studies, clinical phase 1, 2, and 3 studies, and after approval through post-marketing safety surveillance (which may be passive or active).  The importance of the latter is that rare adverse effects, those with a long latency, and those occurring only in subgroups of the general population not studied (e.g., the elderly or immunocompromised) will not likely be identified in clinical phase studies.  An example of an adverse reaction only detected after widespread vaccine use was Guillain-Barré syndrome (GBS) resulting from the 1976 swine flu vaccine.² 

As of October 2, 2020, there are 42 candidate vaccines of different types (including inactivated, viral vector, RNA, DNA, and protein subunit vaccines) in clinical evaluation.³ More information is available on multiple SARS-CoV-2 vaccines in development.⁹ 

Early studies of vaccine candidates have identified common adverse effects. A Phase 1 trial of the mRNA-1273 (Moderna) vaccine found that fatigue, chills, headache, myalgia, and pain at the injection site occurred in over 50 percent of recipients. There were no serious adverse events.⁴ Similarly, a Phase 1/2 trial of two recombinant adenovirus vector vaccines (from Russia) found that “The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and
joint pain (18 [24%]). Again, there were no serious adverse events.⁵ In both studies, there is a very limited period of follow-up and a small number of recipients that could permit assessment of possible long-term adverse effects.
One of the phase III clinical trials (AstraZeneca AZD1222) was halted in early September because of a possible vaccine safety signal. The volunteer, based in Britain, was diagnosed with transverse myelitis. This vaccine candidate is being tested in large-scale Phase 2 and Phase 3 trials in the United States, Britain, Brazil, South Africa and India. After review by the Data Safety Monitoring Board with external vaccine safety experts and the UK national regulatory agency MHRA, the clinical trial was resumed in the UK on the 12 September.⁸

There are concerns about the potential for more serious adverse events—enhanced respiratory disease (ERD) following infection and a subtype of ERD, antibody-dependent enhancement (ADE) following infection after vaccine administration.  There are two mechanisms of ADE, both of which “occur when non-neutralizing antibodies or antibodies at sub-neutralizing levels bind to viral antigens without blocking or clearing infection.” In ADE via enhanced infection, non-neutralizing antibodies bound to the virus enhance infection rates in target cells, such as macrophages, leading to more severe disease.  In the second type described by Lee et al., ADE via enhanced immune activation, binding of non-neutralizing antibody to the virus leads to the formation of immune complexes in lung tissues, which, in turn, lead to “secretion of pro-inflammatory cytokines” and “activation of the complement cascade”. “The ensuing inflammation can lead to airway obstruction and can cause acute respiratory distress syndrome in severe cases.” A recognized example of this type of enhanced respiratory disease results from some infections with measles after measles vaccination and has been seen with vaccines for RSV, dengue, and SARS. “Existing evidence suggests that immune complex formation, complement deposition and local immune activation present the most likely ADE mechanisms in COVID-19 immunopathology.”⁶  

Vaccine developers are well aware of ADE and have pursued approaches that make ADE less likely. This includes selecting specific epitopes within the receptor binding domain of the spike protein as targets for a neutralizing antibody response. It is encouraging that some early clinical trials reports have indicated both a strong neutralizing antibody response and and a strong type 1 helper T cell (T_H1) response, rather than the T_H2 response associated with immunopathology.⁴   

Kostoff et al. discuss the possibility that accelerated COVID-19 vaccine development and deployment might ultimately result in unexpected long-term adverse effects. . The potential adverse consequences of such a mass inoculation with a vaccine not adequately tested for mid‑ and long‑term adverse effects could be substantial.”⁷