Vaccines for COVID-19. Part 1: The Good, the Bad, the Ugly

Vaccines for COVID-19.

There has been a lot of good news on the vaccine front. First, Pfizer announced that its BNT162b2 vaccine was 95% effective against COVID-19 beginning 28 days after the first dose;170 confirmed cases of COVID-19 were evaluated, with 162 observed in the placebo group versus 8 in the vaccine group.

The math: (risk among placebo group – risk among vaccinated group)/risk among placebo group;
If I had all the numbers, I would calculate it for you).

Data for the Pfizer BNT162b2 vaccine also showed:

  • Efficacy: p<0.0001 for primary endpoint (a very statistically significant indication of the efficacy of vaccine)
  • Efficacy was consistent across age, gender, race and ethnicity demographics; observed efficacy in adults over 65 years of age was over 94%
  • Safety: The data milestone required by U.S. Food and Drug Administration (FDA) for Emergency Use Authorization (EUA) has been achieved.

Data demonstrate vaccine was well tolerated across all populations with over 43,000 participants enrolled; no serious safety concerns observed; the only grade 3 adverse event greater than 2% in frequency was fatigue at 3.8% and headache at 2.0%.

Moderna also reported results of its Phase 3 study of mRNA-1273, as the trial met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5%.

Data for the Moderna mRNA-1273 vaccine also showed:

  • Efficacy: p <0.0001 for primary endpoint (a very statically significant indication of the efficacy of the vaccine)
  • The 95 COVID-19 cases included 15 older adults (ages 65+) and 20 participants identifying as being from diverse communities (including 12 Hispanic or LatinX, 4 Black or African Americans, 3 Asian Americans and 1 multiracial).
  • Safety: The interim analysis did not report any significant safety concerns. A review of solicited adverse events indicated that the vaccine was generally well tolerated. The majority of adverse events were mild or moderate in severity. Grade 3 (severe) events greater than or equal to 2% in frequency after the first dose included injection site pain (2.7%), and after the second dose included fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%). These solicited adverse events were generally short-lived.

Results from AstraZeneca’s AZD1222 Covid-19 vaccine (a replication-deficient chimpanzee viral vector based on a weakened version of a common cold adenovirus containing the viral spike protein) were also reported November 23rd. The comparator was a meningococcal vaccine (MenACWY) in two trials and for the first dose of the third trial (saline placebo was used as the comparator in the last dose). Again, these data are not peer reviewed.

The trial used two dosing regimens: (a) a half dose followed by a full dose one month apart; and (b) two full doses one month apart. The efficacy of these dosage cohorts was 90% (n=2,741) and 62% (n=8,895), respectively. The combined analysis resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). In addition:

  • The analysis met its primary endpoint
  • No serious safety events related to the vaccine have been confirmed.
  • AstraZeneca will now seek an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries.

The big question is why there is such a large difference in efficacy between the two dosage regimens. One potential explanation according to Dr Gillies O’Bryan-Tear, Chair, Policy and Communications, Faculty of Pharmaceutical Medicine, is that the body is mounting an anti-vector immune response to the second dose [meaning the adenoviral vector rather than the spike protein genetic material), which is lower if the first dose is reduced; such an immune reaction could reduce the efficacy of the vaccine.

All of this is good news, the more so because both these vaccine approaches are relatively new in the vaccine world.

How long will the protection of the vaccine last?
If you get the vaccine, how long will the protective effect last? A new UK study further suggests that for individuals who have been infected with COVID-19, re-infection may be relatively rare because helper T cells continue to protect most people against the virus for at least 6 months. But, compared with individuals who experienced no symptoms, the T cell responses of those who had symptoms were 50% stronger. Helper T cells, you will recall, not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but also help activate cytotoxic T cells to kill infected target cells. While I think 1 to 2 years immunity is probable, we won’t know for another year or so whether that assumption is correct.

Vaccine Implementation
Both Pfizer and Moderna expect to have tens of millions of vaccine doses available by the end of the year. The first real problem is that the transition in the White House will likely delay rollout. The current Trump administration plan to distribute and give the vaccines to priority groups is not fully fleshed out, and a new administration may be unlikely to implement a previous plan, which means preparations may have to start over after the transition. The second problem is more worrisome.

The past several months we have been concerned about the high percentage of individuals who would refuse to take a COVID-19 vaccine, or were sitting on the fence because of worries about its effectiveness. There is some good new on this front. Recent Gallup and Axios/Ipsos polls conducted in the USA show an increase of about 7-8% in terms of Americans who would get the vaccine once it’s made available. The absolute numbers vary according to how the questions were asked but they’re moving in the right direction, and given the most recent results about safety and effectiveness of the vaccines, it’s likely that those numbers will be up further by the spring of 2021, which should push us toward the magic number of 70-80% immunized (by vaccine or naturally) needed to get R0 of the virus below 1. So, spring of 2021 is a time to look forward to.