HJBR Nov/Dec 2020

HEALTHCARE JOURNAL OF BATON ROUGE I  NOV / DEC 2020 21 1. Safety first! Hundreds of experimental vaccines are under study, including 11 Phase 3 internation- al clinical trials. Five of these Phase 3 trials are open in the U.S., one of which has been paused due to lack of data on a serious ad- verse event (transverse myelitis). Of the five vaccines tested in the U.S., two are mRNA- based, two consist of recombinant adenovi- ruses expressing SARS-CoV2 epitopes and one is protein-based. All but one require two injections. It’s important to remember that unlike medications, approved vaccines are administered to tens or hundreds of millions of healthy people. Hence, even rare adverse events have a significant probability to oc- cur. A serious adverse event (SAE) with a 0.1 percent incidence rate for a vaccine admin- istered to 100million people would translate into 100,000 SAE cases. Hence, the need for large sample sizes (tens of thousands of sub- jects), extensive safety monitoring and care- ful follow-up. Both autoimmune toxicity and viral enhancement are potential side effects to watch for. Toxicity due to antibody-medi- ated enhancement stopped the development of experimental SARS vaccines. 2. How will we determine efficacy? Vaccine clinical trials usually include laboratory endpoints (e.g., neutralizing an- tibody titers, CD8 T-cell responses, etc.) and clinical endpoints, such as decreased disease severity. Intentionally infecting human vol- unteers with virus and determining if they are protected is the surest way to determine whether a vaccine works. However, such an approach is fraught with ethical complica- tions, as the risk of mortality is not zero even among healthy, young subjects. Since CO- VID-19 has highly variable clinical manifesta- tions, proving that vaccinated patients who become infected have less severe symptoms thanmatched unvaccinated controls requires very large clinical trials and enrolling patients with different characteristics and in different age groups. Another complicating factor is human genetic and phenotypic variability. The genes that control our immune systems are extremely polymorphic, and no two indi- viduals other than identical twins are exactly the same from an immunogenetic standpoint. The effectiveness of immune responses is also affected by age and comorbidities as- sociated with chronic inflammation and/or immune suppression. The duration of im- mune responses elicited by vaccines will be a critical variable. Recent results indicate that anti-SARS-CoV2 spike protein antibodies de- cay rapidly after mild infections. This is con- sistent with the fact that natural immunity to other coronaviruses is short-lived. These considerations imply that we can expect sig- nificant individual variability in vaccine re- sponses, and even the best vaccine is unlikely to offer long-term, complete protection to everyone. This wouldn’t necessarily make a vaccine useless, as partial protection may be enough to limit disease severity and de- crease mortality. 3. Will viral evolution outpace vaccines? One important question is whether SARS- CoV2 can partially or completely overcome protective immunity through mutation, as influenza viruses do yearly. Although so far it appears SARS-CoV2 mutates more slowly than influenza viruses, there is clear evidence of multiple novel viral clades emerging through random mutation and natural selection. Arecent study that sequenced over 5000 independent viral isolates confirmed that the D614Gmutation in the Spike protein gene, which was suggested to be associated with higher infectivity, is overtaking the parental gene. Patients infected with viruses carrying this mutation produce higher viral loads. Importantly, this study also found new mutations in the Spike protein gene (S) that would decrease its affinity for neutralizing antibodies and mutations in the RNA- dependent RNA polymerase gene (RdRp) that may produce resistance to Remdesivir. This is not surprising, as rapid mutation and natural selection are exactly what one would expect from a widely distributed RNA virus faced with selective pressure from medications and immunity. Acquired drug resistance is well-known in the case of “We must be prepared to adopt multipronged strategies of containment, prevention, improved diagnosis and treatment to face this emerging threat.”