Short Answer: Boosters are currently being tested, but no data yet

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):

The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines are both approved under Emergency Use Authorization for a schedule of 2 doses (3 weeks apart for BNT162b2 and 4 weeks apart for mRNA-1273).^{CDC Moderna; CDC Pfizer} There are currently no data on using boosted doses of these vaccines, including whether they will be needed and whether they will enhance protection against the mutant viruses that are being observed with increasing frequency.^{CDC Variants} However, this will be an important clinical question to answer in future trials. Moderna has developed a new variant-specific booster against the virus variant from South Africa (mRNA-1273.351), and plans to test (1) mRNA-1273.351 alone, (2) a multivalent booster that combines the original mRNA-1273 and mRNA-1273.351, and (3) a third dose of mRNA-1273.^{Moderna mRNA-1273.351}

Short Answer: Vaccination reduces the risk of developing severe disease, but nonpharmaceutical interventions should still be adhered to

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):
Fortunately, the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines are very effective and are able to prevent symptomatic infection in >94% of patients.^{Pfizer 2020; Moderna 2020} Furthermore, both vaccines dramatically reduce the risk of developing severe symptomatic disease and hospitalization. Indeed, in the Pfizer-BioNTech trial, there were 10 severe cases of COVID-19, 9 of which were in the placebo group and only 1 one of which was in the vaccine group. In the Moderna trial, all 30 severe COVID-19 cases occurred in the placebo group.^{Moderna 2020} The Johnson & Johnson vaccine demonstrated 85% efficacy against severe COVID-19.^{J&J 2021} These data should give us some comfort in returning to normal activities, but note that there are still recommendations for fully vaccinated individuals to maintain nonpharmaceutical interventions such as mask wearing and physical distancing in public or when around unvaccinated, high-risk persons due to the unanswered question of whether vaccinated individuals can still carry the virus and transmit it to others.^{CDC Fully Vaccinated} The CDC specifically states that a fully vaccinated person can gather indoors with other fully vaccinated people without masks and can gather indoors with unvaccinated people from 1 other household without masks, unless any of the unvaccinated people are at increased risk for severe disease.^{CDC Fully Vaccinated} However, these recommendations will vary by country based on many epidemiologic factors.^{CDC Fully Vaccinated}

Short Answer: Typically 10 days, but may be longer for patients with severe disease

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):
The current recommendation from the CDC is that vaccination should be deferred until the person is no longer symptomatic and has completed the recommended isolation period, which is usually 10 days (may be longer for patients with severe disease).^{CDC mRNA Vaccines} The only circumstance for which it is recommended to delay vaccination longer is if the patient received either convalescent plasma or monoclonal antibody therapy.^{CDC mRNA Vaccines} In this scenario, the recommendation is to defer vaccination for at least 90 days due to the possibility that the convalescent plasma or monoclonal antibody will reduce vaccine efficacy.

Short Answer: Yes

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):
Yes, the effectiveness estimates will likely need to be adjusted based on real-world data. In terms of vaccines, efficacy and effectiveness mean 2 very different things. Vaccine efficacy refers to the effect the vaccine has on a predetermined primary endpoint under ideal and controlled circumstances in the setting of a clinical trial. Vaccine effectiveness, however, refers to how well it performs in the real world and how effective it is at preventing admissions to the hospital and death.

Short Answer: Possibly

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):
There is some concern that receiving only 1 of the 2 recommended vaccine doses, or prolonging the time interval between the 2 doses, could cause mutations in the virus, although this has not been formally assessed. The concern arises when we consider that subtherapeutic, or low levels, of an antibody may still allow for viral replication. We are very familiar with this concept in HIV where a suboptimal level of antiretroviral drug drives the development of resistance through the accumulation of mutations in the virus.^{Tang 2012} Both currently recommended mRNA COVID-19 vaccines were authorized based on a 2-dose schedule, and the FDA recommends extreme caution when amending this schedule since data are not sufficient to support this approach.^{FDA Statement}

It is worth highlighting, however, that the recently authorized Johnson & Johnson vaccine is a single-shot vaccine.^{J&J 2021}

Short Answer: Not currently recommended

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):
Although this strategy may be viable, there are currently no data to support this approach, and thus, it is currently not recommended.^{CDC mRNA Vaccines}

Short answer: Likely

Roger Paredes, MD, PhD (1/14/2021):

Short answer: Not likely

Roger Paredes, MD, PhD (1/14/2021):

Unfortunately, it seems as though the virus is spreading too rapidly at this time in both Europe and the United States with these new variants—the so-called third wave—to curb the spread with population immunity via vaccination. Instead, I believe we must increase social distancing measures and perhaps implement more lockdowns, although I am aware that this is highly controversial. Such measures and lockdowns can then be eased with higher vaccination coverage, which will likely be reached in richer countries sooner than in poorer ones.

Short answer: Both currently available vaccines are more than 94% efficacious

Roger Paredes, MD, PhD (1/14/2021):

Short answer: Vaccination should be deferred in patient testing positive for COVID-19 until symptoms have resolved or criteria have been met to discontinue isolation

Roger Paredes, MD, PhD (1/14/2021):

Short answer: Both doses are recommended

Roger Paredes, MD, PhD (1/14/2021):

Short answer: Unknown

Vikramjit Mukherjee, MD (12/18/2020):

In my mind, having detectable antibodies demonstrates that a patient has been infected with SARS-CoV-2 in the past, but nothing else. It does not tell us whether those antibodies are protective, nor whether that individual should receive the vaccine or not. There are no data to show that having detectable antibodies is protective against a second infection, and we know of case reports of reinfection.^{Tillett 2020; To 2020; Goldman} I would strongly urge our colleagues and patients to continue taking all precautions to prevent infection as if you do not have antibodies. Wear proper personal protective equipment, practice social distancing and handwashing, and so on.

Short answer: Unknown

Vikramjit Mukherjee, MD (12/18/2020):

This is a critical question. Currently, we do not know whether these 2 vaccines prevent infection with SARS-CoV-2. What we do know is that they provide approximately 95% protection from clinical disease after 2 doses.^{Pollack 2020; Moderna Press Release} That is, they prevent symptomatic COVID-19 disease. In the phase III vaccine trials, efficacy was evaluated by comparing how many people in the vaccine arm vs the placebo arm presented with symptoms of COVID-19 and then tested positive by RT-PCR. Again, I emphasize that they looked for prevention of clinical disease, not infection. This is important because we know that approximately 30% of infected individuals will be asymptomatic, but so far these trials have not reported data on asymptomatic infections.^Byambasuren

Therefore, while I urge everyone to take the vaccine at your earliest opportunity, it is not the time to let your guard down. Maintain other precautions even after vaccination to prevent inadvertent transmission to others until we reach herd immunity or until we know that the vaccines prevent all infections, not just symptomatic infections.

Short answer: Some efficacy reported but lower than after 2 doses

Roger Paredes, MD, PhD (1/14/2021):

The first dose of both of the currently available vaccines elicits a rapid immune response that offers substantial protection. Indeed, investigators reported that the BNT162b2 (Pfizer-BioNTech) vaccine resulted in 52% efficacy before the second dose was administered (21 days after the first dose),^{Pollack 2020} and the mRNA-1273 (Moderna) vaccine was 80% effective in individuals who had received only 1 dose. ^{FDA Moderna} If we view these results in light of previous discussions where regulatory agencies were willing to accept a 50% efficacy to achieve licensing, these response rates are certainly adequate. Therefore, because vaccine quantities remain limited, some countries have discussed vaccinating a larger proportion of individuals with a single dose, rather than vaccinating fewer individuals with 2 doses. Nevertheless, the FDA recommends extreme caution when amending these vaccine schedules since data are not sufficient to support this approach.^{FDA Statement} Encouragingly, other vaccines currently under investigation may require only a single dose.^{Sadoff 2021}

Vikramjit Mukherjee, MD (12/18/2020):

It was reported that the BNT162b2 (Pfizer-BioNTech) vaccine resulted in 52% efficacy before the second dose was administered (21 days after the first dose).^{Pollack 2020} In the mRNA-1273 (Moderna) vaccine trial, a subanalysis found that the vaccine was 80% effective in individuals who had received only 1 dose.^{FDA 2020} Hence, the first dose elicits a rapid immune response that offers some protection. However, it will be important for individuals to receive both doses for full protection. 

Short answer: Unknown

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):

Pregnant women were not included in either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine trials, so we do not have data on the safety of these mRNA vaccines for pregnant women or their fetuses. The current recommendation is that COVID-19 vaccination be discussed at an individual level with each pregnant woman.^{CDC Pregnancy} While it is unlikely that the COVID-19 vaccines will have any adverse effects specific to pregnant women or their fetuses, data are currently being collected in Phase IV trials to help us answer this question.

Vikramjit Mukherjee, MD (12/18/2020):

That population was not included in either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine trials, so we do not have data on the safety of these mRNA vaccines for pregnant women or their fetuses.

Short answer: Yes

Roger Paredes, MD, PhD (1/14/2021):

Current guidelines recommend that individuals who have recovered from COVID-19 should receive the vaccination when available because reinfection, especially with one of the new variants, may be possible.^{CDC mRNA Vaccines} This should not depend on antibody status, as having positive antibodies does not always correlate with having neutralizing antibodies.^{FDA Neutralizing Antibody Test} In addition, we do not currently know the titers of neutralizing antibodies adequate to confer protection.

Vikramjit Mukherjee, MD (12/18/2020):

Current interim guidance from the CDC recommends that COVID-19 vaccination should be offered regardless of history of SARS-CoV-2 infection.^{CDC mRNA Vaccines} Moreover, a previous SARS-CoV-2 infection does not necessarily prevent subsequent reinfection. Although rare, we have seen case reports of reinfection, including some cases that were more severe upon reinfection.^{Tillett 2020; To 2020; Goldman} Vaccination could prevent reinfection for individuals with prior COVID-19.

Short answer: Randomization and double-blind design

Jens D. Lundgren, MD, DMSc (11/19/20):

In the Pfizer-BioNTech phase III trial investigating BNT162b2, 43,448 patients were enrolled, but only a small number of them, 170 enrollees, actually contracted the infection.^{Pollack 2020} Similarly, Moderna released final efficacy analyses results stating that their trial observed 196 cases among 30,000 participants.^{Moderna 2020} These reported incidences of infection are somewhat low. When you plan a vaccine trial, you want to enroll people in areas where the virus is spreading rapidly so you can accumulate data quickly, but those locations may be hard to predict. The more follow-up there is, the more events will accumulate.

What do we know now about potential bias? Both the Moderna and Pfizer-BioNTech trials were large, double-blind, and placebo-controlled, meaning that the people who participated in the studies were not aware if they received the vaccine or placebo. This design suggests that the 2 groups were unlikely to have behaved differently based on their perceived risk, so we assume that their risk of exposure would be similar—one of several assumptions made when assessing vaccine efficacy. There were no differences in reported demographics between the vaccine and placebo recipients in the Pfizer-BioNTech study; however, the publication does not include factors that may relate to exposure (high-risk careers, work environment, etc).^{Pollack 2020}

Short answer: Participants experienced injection site pain, fatigue, headache, and fever

Roger Paredes, MD, PhD (1/14/2021):

Overall, both of the currently available vaccines for COVID-19 have been found to be very safe. The most frequent adverse events in both vaccine trials was mild injection site pain, similar to the influenza vaccine.^{Pollack 2020; FDA Moderna} Most recently, several cases of anaphylaxis have been reported after receipt of the first doses of both vaccines, but overall, they appear to be rare. Indeed, the CDC reported a rate of 11.1 cases of anaphylaxis per million doses of the BNT162b2 (Pfizer-BioNTech) vaccine administered and 2.5 cases of anaphylaxis per million doses of the mRNA-1273 (Moderna) administered.^{CDC Allergic Reactions Pfizer; CDC Allergic Reactions Moderna} Although these events appear to be rare, the CDC notes that “comparisons of anaphylaxis risk with that associated with non–COVID-19 vaccines are constrained at this time by the limited data available this early in the COVID-19 vaccination program.”^{CDC Allergic Reactions Pfizer; CDC Allergic Reactions Moderna}

Regarding long-term safety, we do not have data yet to fully know how safe these vaccines are, but understanding how RNA vaccines work should provide some reassurance. For example, RNA is very unstable, so after the vaccine is administered, the RNA is only present in your body for a few days before it gets degraded; it does not integrate into the genome.^{Wadhwa 2020} Thereafter, what is observed is immune stimulation exerted by that mRNA.

Jens D. Lundgren, MD, DMSc (11/19/20):

The phase I and II trials consistently showed more adverse events with the vaccines compared with the placebos and more adverse events associated with the second injection compared with the first.^{Jackson 2020; Mulligan 2020} Participants reported typical vaccine responses such as fatigue, injection site reactions, and chills. In safety data published for the Pfizer-BioNTech phase III trial investigating BNT162b2, mild to moderate pain at the injection site was the most commonly reported local reaction.^{Pollack 2020} Pain following the second dose was reported less frequently among participants older than 55 years of age (66%) than among younger participants (78%). The most commonly reported systemic events were fatigue and headache (59% and 52% after the second dose, respectively). There were 4 vaccine-related serious adverse events reported among BNT162b2 recipients—shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia. We await publication of safety data from the Moderna phase III trial investigating mRNA-1273.

Vikramjit Mukherjee, MD (12/18/2020):

The most frequent adverse event in both vaccine trials was mild injection-site pain, similar to the influenza vaccine.^{Pollack 2020; FDA 2020} Mild cases of fatigue, headache, and fever were also common in both trials. These were low-grade events, with very few people having to take time off from work or having to rest at home. Severe (grade ≥ 3) events were rare in both trials.

There have been reports of rare occurrences of hypersensitivity reactions after vaccination.^{CDC Reactions} This seems to be extremely uncommon and limited to patients who have a predisposition to anaphylactic reactions from previous vaccinations. If you have had an anaphylactic reaction to a previous vaccination, the CDC recommends that you talk to your healthcare provider before receiving the currently authorized vaccines. In the absence of that, and especially knowing the consequences of not being immunized, my inclination would be for everyone to take the vaccine as soon as you are eligible.

Short answer: Prevention of symptomatic COVID-19

Jens D. Lundgren, MD, DMSc (11/19/20):

The primary endpoint in both trials was prevention of symptomatic infection.^{Pfizer 2020; Moderna 2020} The intent was to randomize healthy participants to receive the vaccine or placebo, and count how many in each arm became ill with symptomatic COVID-19. The trials also included people at high risk of severe disease and/or hospitalization.  

In the Pfizer-BioNTech trial investigating BNT162b2, there were 170 cases of COVID-19, 162 in the placebo group and 8 in the vaccine group, resulting in a vaccine efficacy rate of 95%. There were 10 severe cases of COVID-19, 9 in the placebo group and 1 in the vaccine group. In the Moderna trial, there were 196 COVID-19 cases, of which 185 cases were observed in the placebo group vs 11 cases in the mRNA-1273 group, resulting in a vaccine efficacy of 94.1%. In addition, all 30 severe COVID-19 cases occurred in the placebo group.^{Moderna 2020}

At this point, all we know is that the vaccines are providing protective immunity from clinical disease—it is not yet known if the vaccines prevent infection or prevent subsequent transmission if a vaccinated person becomes infected. As these studies are analyzed further, it may be possible to identify a minimal antibody titer of protection that is associated with little or no risk of infection. Then we can investigate the kinetics of antibody changes after vaccination, particularly how quickly antibodies drop below a protective threshold, which will provide information on if a third vaccine injection or booster will be needed in the future. 

Short answer: Natural immunity declines rapidly, but vaccine-induced immunity could be more durable

Sharon R. Lewin, AO, FRACP, FAHMS (2/2/2021):

Unfortunately, we do not currently know the answer to that. The longest published data that I have seen at the moment on antibodies (if you assume that antibodies are the appropriate biomarker for protection, which we believe they are) followed people for 119 days following receipt of the Moderna vaccine.^{Widge 2021} Those data demonstrated that although antibody levels decreased slightly, serum neutralizing antibodies were detected in all the participants in all age groups at Day 119. We must await further longitudinal data to know the full duration of protection.

Roger Paredes, MD, PhD (1/14/2021):

Unfortunately, we really do not know the answer to this key question for SARS-CoV-2 at this time. What we do know is that protective immunity from seasonal coronaviruses is short-lived, from a few months up to 1 year, and thus reinfections are common.^{Edridge 2020} For Middle East Respiratory Syndrome and SARS-CoV-1 viruses, however, immunity is longer lasting—up to several years in most people.^{Sariol 2020} It is unclear where SARS-CoV-2 will fall on this spectrum. Although the follow-up time to date is short—only 2 months—it is encouraging that we have not seen evidence of a plateauing effect as yet in the vaccines that have been administered. Therefore, there is currently no evidence that vaccine efficacy is waning.

Jens D. Lundgren, MD, DMSc (11/19/20):

The best data we have, of course, are the data on the decline of natural immunity, both antibodies and leukocytes. The antibodies seem to decline fairly rapidly over the first 3 to 4 months.^{Ibarrondo 2020; Wang 2020} Whether the vaccine-induced antibodies will have the same kinetics remains unknown. They seem to start from a higher level in vaccinated patients, compared with patients who have recovered from acute COVID-19.^{Jackson 2020} Based on those data, it is possible that the vaccine antibody response may be more durable than the response induced by natural infection.  

T-cell immunity is slightly more complicated to study. It seems that these messenger RNA vaccines are inducing T-cell immunity, particularly a Th1-type response.^{Jackson 2020} It is unlikely that T-cell immunity will provide protective immunity on its own. However, durable T-cell immunity could contribute to a durable protective response, but the longevity of these T-cell responses remains to be seen. 

Short answer: Not yet known

Roger Paredes, MD, PhD (1/14/2021):

Although there is a theoretical risk of antibody-dependent enhancement of disease if a person recently treated with monoclonal antibodies receives a COVID-19 vaccine, there is currently no evidence to support its occurrence.^{Lee 2020} Our group is personally involved in several clinical trials with monoclonal antibodies through the ACTIV-3 collaboration, which is funded by the National Institute of Health, and we have not seen any evidence of antibody-dependent enhancement. Nevertheless, we must be vigilant of the potential for this outcome when conducting these clinical trials.

Jens D. Lundgren, MD, DMSc (11/19/20):

For some other infectious diseases, such as dengue infection, those who have antibodies can have a worse disease course compared with those without.^{Shukla 2020} There are currently no data suggesting that this occurs in COVID-19. However, this should be investigated.

Antibody-dependent enhancement is unlikely to occur early on, while the antibody titers are highest. However, when the antibodies decline below a protective titer but are still present, it is possible antibody-dependent enhancement could occur.^{Arvin 2020} We do not expect to see this happen with COVID-19, but we cannot rule it out.

Short answer: It is possible. We need more data on children.

Jens D. Lundgren, MD, DMSc (11/19/20):

The immune response is different in children, and whether that is good or bad remains unknown. Certainly, there have been children who have had a hyperinflammatory response to COVID-19.^{Hobbs 2020} Whether the vaccine will result in a different safety profile in children compared with adults is not yet known, as the initial trials did not include children. Pfizer-BioNTech is starting to include children 12 years of age and older in clinical trials investigating BNTB162b2.^NCT04368728 I think there need to be robust data before we consider mass vaccination in children.

Short answer: Yes

Jens D. Lundgren, MD, DMSc (11/19/20):

The vaccine trials have been attempting to include people of diverse ethnic backgrounds in the study populations. In the Pfizer-BioNTech and Moderna phase III clinical trials, 42% and 37%of the volunteers had diverse ethnic backgrounds, respectively.^{Pfizer 2020; Moderna 2020} Published analyses of the phase III Pfizer-BioNTech trial demonstrated that efficacy of BNT162b2 among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population.^{Pollack 2020} Safety was reported by age subgroup, and common local and systemic reactions such as pain, headache, fatigue, and fever were reported less frequently for patients older than 55 years. These data do not suggest any safety signals for any one subgroup; however, more data are needed.

Short answer: It’s complicated

Jens D. Lundgren, MD, DMSc (11/19/20):

I think the concern is mostly whether the vaccine will be effective in these populations. Certainly, one concern is that patients with an immunosuppressive disease or on an immunosuppressive therapy may not have enough B cells to be activated. However, I do not foresee a safety issue for immunocompromised patients with the Pfizer-BioNTech or Moderna vaccines, as they consist of mRNA and are not live or attenuated virus. The US Centers for Disease Control and Prevention state that immunocompromised “individuals may still receive COVID-19 vaccination if they have no contraindications to vaccination. However, they should be counseled about the unknown vaccine safety profile and effectiveness in immunocompromised populations, as well as the potential for reduced immune responses and the need to continue to follow all current guidance to protect themselves against COVID-19.”^{CDC mRNA Vaccines}