VACCINES — MECHANISM, EFFICACY, SAFETY
Two vaccines are currently available in the United States, one developed by Pfizer/BioNTech (BNT162b2) and the other by Moderna (mRNA-1273); both vaccines work via a novel messenger RNA (mRNA) mechanism. In these vaccines, the mRNA carries instructions to make the SARS-CoV-2 “spike” protein — the prickly projections on the surface of the virus, which is structured like those rubber balls that dogs love to chase or like the quills of a porcupine.
Once the vaccine is injected, the mRNA is taken up by the macrophages near the injection site and instructs those cells to make the spike protein. The spike protein then appears on the surface of the macrophages, inducing an immune response that mimics the way we fight off infections and protects us from natural infection with SARS-CoV-2. Enzymes in the body then degrade and dispose of the mRNA. No live virus is involved, and no genetic material enters the nucleus of the cells.
Although these are the first mRNA vaccines to be broadly tested and used in clinical practice, scientists have been working on mRNA vaccines for years. And despite this wonderful parody piece. opens in new tab saying that the technology is “obvious,” in fact the breakthrough insight that put the mRNA inside a lipid coating to prevent it from degrading is quite brilliant — and yes, this may be the first time the New England Journal of Medicine has referenced a piece in The Onion. (Last reviewed/updated on 27 Jan 2021)
Both vaccines are remarkably effective. In large clinical trials (Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. opens in new tab by L.R. Baden et al., and Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. opens in new tab by F.P. Polack et al.) that enrolled tens of thousands of people, the vaccines lowered the chance of developing Covid-19 by around 95% as compared with placebo injections. As summarized quite accurately in this XKCD cartoon. opens in new tab, sometimes data are so strong we don’t even have to do a statistical analysis — that’s what happened with both of these clinical trials. The results were that good.
Although we consider data from randomized, placebo-controlled trials to be the strongest form of clinical evidence, additional details make the results even more compelling. First, the vaccines prevented not only any disease due to SARS-CoV-2, but — quite importantly — severe disease. Prevention of severe disease could convert Covid-19 from the global threat it is now into more of a nuisance, like the common cold. Second, the studies enrolled participants who were quite representative of the U.S. population — age, sex, race, and ethnicity all broadly included. Third, while both vaccines are given as two doses, some protection became apparent just 10 to 14 days after the first dose.
The efficacy noted after the first dose has raised questions about whether we should be vaccinating twice as many people with one dose rather than giving people the full two-dose schedule. opens in new tab. However, the 95% vaccine efficacy results come after the second dose, which boosts the immune response and is likely to make it more durable. For now, in the United States, the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) recommend proceeding with the two-dose schedule whenever possible.
Overall, these impressive results put the two mRNA vaccines up there with our most effective vaccines to date — more like measles than influenza vaccines, at least in the short term. The protection is far better than anyone anticipated, which is why many of us specialists in infectious diseases, virology, immunology, and public health become downright giddy when asked to discuss the vaccine’s efficacy.
An important caveat to the favorable efficacy results in the clinical trials is that the performance of the vaccines in clinical practice — the effectiveness — may be different. Although the study population in both studies includes people at high risk for Covid-19 complications, participants had to be clinically stable and sufficiently healthy to come in for their study visits. We do not yet know how effective the vaccines will be in a sicker population, such as the frail older people of advanced age living in nursing homes, or the severely immunocompromised. Population-based studies that include hundreds of thousands of people ultimately will give us a better sense of these “real world” data. (Last reviewed/updated on 27 Jan 2021)
Since the vaccines have been tested only since the summer of 2020, we do not have information about the durability of protection. Data from the phase 1 trial of the Moderna vaccine suggested that neutralizing antibodies persisted for nearly 4 months. opens in new tab, with titers declining slightly over time. Given the absence of information on how long the vaccines will be protective, there is currently no specific recommendation for booster doses. (Last reviewed/updated on 27 Jan 2021)
Currently there is limited information on how effective the mRNA vaccines will be against emerging strains of SARS-CoV-2. Both clinical trials preceded the identification of the major variants present now in multiple countries around the world. Preliminary studies (not yet peer reviewed and published) suggest that the vaccines might be more protective against some of the variants than others (see here. opens in new tab, here. opens in new tab, here. opens in new tab, here. opens in new tab, and here. opens in new tab). An important limitation of these studies (which used samples from immunized or recovered people in the lab to assess neutralization) is that protection afforded by vaccination is more complex than simply measuring antibody responses. Molecular sequencing of the viruses from incident cases of Covid-19 that occur after vaccination will be important to help understand this important issue.
In one study, the Moderna vaccine’s level of neutralizing antibody titers was six times lower with the B.1.351 variant than with earlier variants. Though the company says the titers still should be protective, they are developing a booster vaccine specifically to address this difference. Nonetheless, from a practical perspective, the discovery of these variants does not change the basic recommendations for vaccination. Specifically, right now it is not recommended that people wait for a new or changed vaccine in the hope that it will be more effective against emerging SARS-CoV-2 variants. (Last reviewed/updated on 29 Jan 2021)
Many commentaries on the results of the vaccine clinical trials cite a lack of information on asymptomatic infection as a limitation in our knowledge about the vaccines’ effectiveness. Indeed, this is a theoretical concern, since up to 40% of people who get infected with SARS-CoV-2 have no symptoms but may still transmit the virus to others.
So, until we know whether the vaccines protect against asymptomatic infection, we should continue to emphasize to our patients that vaccination does not allow us to stop other important measures to prevent the spread of Covid-19. We need to continue social distancing, masking, avoiding crowded indoor settings, and regular hand washing.
There are several good reasons to be optimistic about the vaccines’ effect on disease transmission. First, in the Moderna trial. opens in new tab, participants underwent nasopharyngeal swab PCR testing at baseline and again at week 4, when they returned for their second dose. Among those who were negative at baseline and without symptoms, 39 (0.3%) in the placebo group and 15 (0.1%) in the mRNA-1273 group had nasopharyngeal swabs that were positive for SARS-CoV-2 by PCR at week 4. These data suggest that even after one dose, the vaccine has a protective effect in preventing asymptomatic infection.
Second, findings from population-based studies now suggest that people without symptoms are less likely to transmit the virus to others. Third, many vaccines in wide use powerfully protect against both disease and transmission, so much so that infection control is one of the main motivators behind some vaccine policies. opens in new tab.
Since originally posting these comments, some of my colleagues have reminded me that certain vaccines allow asymptomatic colonization, and no doubt this will sometimes be true about the Covid-19 vaccines. Plus, the protective effect will never be 100%, which is why while case numbers are still high, we still recommend the use of social distancing and masking in public. These caveats notwithstanding, the likelihood that these vaccines will reduce the capacity to transmit the virus to others remains excellent. (Last reviewed/updated on 27 Jan 2021)
Overall, both mRNA vaccines are quite safe — that’s the good news, and it should be the dominant message for our patients. But no vaccine (actually, nothing in medicine) is 100% safe.
Before discussing side effects, we need to acknowledge that the safety of Covid-19 vaccines will be in the spotlight for some time — these are new vaccines for a new disease. Rare events will appear in the news, amplifying attention and worry disproportionate to the actual risk. Our task will be to put these uncommon events into perspective, underscoring that these risks are far lower than the risk of getting sick with Covid-19.
These first two vaccines are classified as “reactogenic” — meaning that they will cause some side effects in most people who receive them, reflective of the brisk immune response they generate. In clinical practice, we should put these vaccines in the same side-effect category as the recombinant shingles vaccine (Shingrix) rather than the annual flu vaccine.
The most common side effect is pain at the injection site, especially in the 12 to 24 hours after administration. Around 1% of participants in the trials categorized the pain as “severe.” Fatigue and headache are other relatively common side effects; high fevers are less common. These side effects generally resolve within a couple of days and are responsive to acetaminophen or a nonsteroidal antiinflammatory drug such as ibuprofen. In general, side effects are more common in younger vaccine recipients than in older ones, with the second shot inducing more side effects than the first.
Some people receiving the vaccines experience erythema, warmth, and pruritus over or near the injection site, occuring in a delayed fashion, typically 5 to 14 days after the shot. The symptoms last a few days and are not a contraindication to receiving the second shot. Some have been treated with oral antihistamines and topical steroids.
In the clinical trials, Bell’s palsy was reported more frequently in vaccine recipients than in controls, but there was not a sufficiently large number of cases to conclude that this was beyond what would naturally be observed in populations of this size by chance. There were no cases of Guillain–Barré syndrome or transverse myelitis.
Although hypersensitivity occurred equally in the placebo and vaccine groups in both trials, after distribution of the vaccines in the United Kingdom and the United States, reports emerged of vaccine recipients experiencing severe allergic reactions (anaphylaxis) shortly after receiving their first dose. opens in new tab. The current leading suspect in causing these reactions is polyethylene glycol, a compound present in both vaccines. Because of these rare events, administration of the vaccines includes a period of 15 minutes of observation after vaccination — 30 minutes for those with a history of severe allergic reactions of any sort.
It’s critically important to emphasize that these allergic reactions are uncommon — the current estimate is that anaphylaxis will occur with the Pfizer vaccine at approximately 6 cases per 1 million doses. opens in new tab, and with the Moderna vaccine at roughly 2 per 1 million. Although these rates of severe allergic reactions are higher than those with other vaccines, they are substantially lower than the rate reported with penicillin, which is estimated to be 1 in 5000. But since severe penicillin allergies don’t turn up as news stories, our challenge will be to contextualize this risk. (Last reviewed/updated on 27 Jan 2021)
The remarkably fast pace of vaccine development means that we have only months, not years, of follow-up. (Both mRNA clinical trials started in the summer of 2020.) But with other immunizations, severe reactions typically occur within days or weeks after administration. Long-term side effects with vaccines are fortunately quite rare, with putative associations later debunked by carefully done population-based studies.
Further safety data on both vaccines will be reported to the Vaccine Adverse Event Reporting System (VAERS). opens in new tab. This program is an existing national early warning system that was set up to detect possible safety problems in any licensed vaccine and has been in operation since 1990. In addition, the CDC has its own smartphone-based tool, which uses texting and a Web-based survey to collect information right after patients receive their Covid-19 vaccine. (Last reviewed/updated on 27 Jan 2021)
After careful review of all the primary safety and efficacy data from the phase 3 clinical trials, the FDA granted both vaccines Emergency Use Authorization (EUA). opens in new tab — the Pfizer/BioNTech vaccine on December 11, 2020, and the Moderna vaccine on December 18. Although this is not technically the full licensure that drugs and vaccines typically get, the director of the branch of the FDA that oversees vaccines says that the scrutiny of the data for emergency use was similar to what’s needed for full approval.
Shipments of the vaccines are sent to the states on the basis of population and are coordinated by the federal government. The states implement a strategy for distributing them, using criteria adapted from guidelines issued by Advisory Committee on Immunization Practices (ACIP). opens in new tab. The ACIP is the group charged with making recommendations to the CDC on immunizations and includes a broad range of experts in vaccines and public health. Its deliberations are summarized on the CDC website. opens in new tab; in addition, the actual meetings were taped and can be viewed on YouTube, in case you want something to watch in place of cute puppy videos.
Vaccine allocations and policies differ from state to state. However, they mostly follow the ACIP recommendations to prioritize (1) health care personnel and (2) residents of long-term care facilities in the initial phase of the Covid-19 vaccination program. A broad overview of each state’s distribution plan is summarized at the National Academy for State Health Policies website. opens in new tab; for more details, individual state departments of public health have additional information.
It is important to note that “health care personnel” includes more than just clinicians. It also includes the many people who work in health care facilities who may be exposed to Covid-19 at the workplace or who interact with patients at any time, including staff in dietary, transport, laundry, engineering, and other services. (Last reviewed/updated on 27 Jan 2021)
Since policies on distribution of Covid-19 vaccines vary by state, the answer differs depending on your site of practice. For example, in Massachusetts we are currently in Phase 1 of vaccine administration, which limits Covid-19 vaccines to these groups. opens in new tab:
As a result, in Massachusetts we cannot at present call our patients and advise them on exactly when and where to go for their vaccine. Things may be different in your state — check your state’s department of public health for local policies. Here’s the policy in Missouri. opens in new tab, to choose one random example.
On the basis of predicted supply — and potential approval of other vaccines — the projected timeline for offering the vaccine to additional patients in my state, Massachusetts, will begin in February 2021, with prioritization of patients who are at highest risk for adverse outcomes from Covid-19 and certain other essential workers:
By April, the supply of vaccine should be sufficient for the general population. But again, because policies and distribution of Covid-19 vaccines vary by state, your timeline may differ depending on your site of practice. Check with your state and local departments of health. (Last reviewed/updated on 27 Jan 2021)