Hello all,

As you're all no doubt aware, vaccines have now been rolling out for several months, and we wanted to take some time to answer some commonly asked questions about what we've learned about the COVID-19 vaccines and to go over some of the recommendations about who should get vaccinated, what to expect, and usage of medications around vaccination.

If you have any questions, we're happy to answer them in the comments!

Special thanks to /u/YourWebcam for their help in research for this post!

What do we know about the efficacy and safety of the COVID-19 vaccines?

As of early December, we had trial data showing that the Pfizer/BioNTech and Moderna mRNA vaccines were both highly effective when administered in a two-dose regimen, reaching efficacies of roughly 94-95% in preventing symptomatic COVID-19. We also had trial data (albeit with many caveats) suggesting that the Oxford/AstraZeneca vaccine had an efficacy of roughly 62% in preventing COVID-19 with two full doses and a standard 4 week dosing schedule; some small subgroup analyses suggested potentially higher efficacies with different doses, though this was complicated due to differences in sample size, population, and dosing time.

Since then, we have continued to learn about the efficacy and safety of the vaccines, both from clinical trials and from the broader rollout of the vaccines to the general public.

Oxford/AstraZeneca

As of early December, clinical trial data suggested that the Oxford/AstraZeneca had an efficacy of roughly 62% in preventing symptomatic COVID-19, with the standard dosages and a four week gap between doses. Most recently, in the United States, a Phase 3 trial found that the vaccine was 76% efficacious in preventing symptomatic COVID-19 and 100% efficacious in preventing hospitalization and death with no significant safety concerns; it is expected that the vaccine will be submitted for Emergency Use Authorization in early April.

Efficacy of One Dose

In their initial rollout, some nations chose to pursue a strategy of broadly administering the first dose to a greater number of people and planning to administer the second dose within 12 weeks rather than at four weeks.

To assess this strategy, researchers ran a clinical trial to answer two questions. First, the researchers wanted to determine whether administering a second dose after 12 weeks would result in robust protection against COVID-19. Second, the researchers wanted to determine whether one dose of the vaccine would offer adequate protection for at least 12 weeks.

The data from this trial, which was published in The Lancet, had positive findings on both of these questions. On the first point, the study found that after a 12 week administration schedule, the vaccine had an efficacy roughly 81%, compared to an efficacy of 55% when the second dose was administered within 6 weeks (though the confidence intervals overlapped between the two estimates). As such, the data suggested that at the very least, there was no significant difference between administering the vaccine within 6 weeks as opposed to delaying the vaccine for 12 weeks -- and potentially suggested a higher efficacy in the latter case. On the question of protection from a single dose, the authors found that the vaccine had an efficacy of 76% between the first dose and the second dose, suggesting that the first dose of the Oxford/AstraZeneca vaccine offers enough protection to warrant delaying the second dose to 12 weeks if needed. Finally, in both these trials, the vaccine had 100% efficacy in preventing hospitalization and death from COVID-19.

These effect sizes were borne out in practice as well. In an analysis of the effectiveness of the vaccine as it was rolled out in England through mid-February, it was found that this vaccine had a 60-73% efficacy in preventing symptomatic disease in individuals over the age of 70 after one dose, with that single dose of the vaccine estimated to be 80% effective at preventing hospitalization.

Efficacy Against Variants

Some studies, though limited in number and scope, have perfunctorily assessed efficacy of this vaccine against different variants of the virus. In the lab, one study focusing on hamsters found that the vaccine was effective against both the B.1.1.7 (UK variant) and B.1.351 (South African variant) lineages of COVID-19. Studies of the efficacy of the vaccine in practice are more limited. One [study](Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7)) out of the UK found that this vaccine had similar efficacy between B.1.1.7 and non-B.1.1.7 lineages of COVID-19, suggesting that the Oxford/AstraZeneca vaccine will be efficacious against B.1.1.7. However, other studies focusing on the B.1.351 variant did not show efficacy of the vaccine in preventing mild-to-moderate COVID-19, though it is important to note that this study was small and likely very underpowered to detect any differences. Nonetheless, this suggests that this vaccine might potentially be less effective against the B.1.351 variant, though more research is needed on this point.

Safety and Concerns about Clotting

In March 2021, some concerns were raised about the safety of the Oxford/AstraZeneca vaccine after some reports of clotting abnormalities across Europe. In response, though the European Medical Agency urged otherwise, many European nations elected to temporarily suspend vaccination with this vaccine for several days.

Many of the reported cases consisted of deep vein thromboses and pulmonary embolisms, which were occurring at roughly the rate expected for the general population. And indeed, in the United Kingdom, there has been no evidence of increased clotting abnormalities or thrombosis in the vaccinated population. However, in roughly 30 individuals across Europe, there have been reports of other conditions, including cerebral venous thromboses and thrombosis with concurrent thrombocytopenia (low platelet count) and bleeding. It is still not known that these case reports are significantly above those expected in the general population as a whole; it is important to bear in mind that millions of individuals have received this vaccine to date, and the anticipated incidence is roughly in the single digits per million individuals vaccinated. However, some early research suggests that these cases bear some characteristics of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), a condition in which the vaccine stimulates an immune response that causes platelets to form clots and become depleted. This condition is treatable with anticoagulants and immunoglobulin therapy, and it appears to occur primarily in younger populations -- though again, it is important to note that the incidence is on the order of a few cases per million vaccinated individuals.

Given the extremely low risk of this condition and the significantly greater benefit that the vaccine provides in preventing COVID-19, the European Medical Agency has stated that the benefits of the vaccine greatly outweigh its risks, even in younger individuals. Younger individuals, though less susceptible to COVID-19 than the elderly, still bear some risk from COVID-19, and that risk is considerably higher than the risk presented by these very infrequent clotting abnormalities. As such, the European Medical Agency has urged continued vaccination using the Oxford/AstraZeneca vaccine.

Pfizer/BioNTech

In late 2020, clinical trial data showed that the Pfizer/BioNTech vaccine was roughly 95% efficacious in preventing symptomatic COVID-19 in individuals aged 16 or older, with more recent continued data from their trial showing that the vaccine remained effective even at six months after vaccination. More recently, the company has announced that its trial of individuals aged 12-15 had similarly high efficacy and safety. On the basis of this data, this vaccine was widely authorized for use worldwide and has since been distributed to tens, if not hundreds, of millions of people. This has allowed for study of the effectiveness of the Pfizer/BioNTech vaccine in preventing COVID-19 in practice.

Efficacy in Practice

Much of the data on the effectiveness of the Pfizer/BioNTech vaccine in practice has come from Israel, where the vaccine has been rolled out broadly to a large proportion of its population. Here, we have found that the vaccine has been highly effective across the board. Two weeks after the second dose of the vaccine, it was reported that the vaccine is roughly 98% effective at preventing symptomatic COVID-19, with roughly 99% or greater efficacy at preventing severe disease, hospitalization, or death from COVID-19. More recent reports have had similar findings, suggesting 97% efficacy or greater at preventing symptomatic COVID-19, hospitalization, and death. Notably, these latter reports also found a 94% decrease in asymptomatic COVID-19 infections.

The SIREN study measured the efficacy of the Pfizer/BioNTech COVID-19 vaccine in a set of healthcare workers in the United Kingdom, who were regularly tested for COVID-19 to detect both symptomatic and asymptomatic infections. They found, in total, that the vaccine was roughly 86% effective in preventing a COVID-19 infection (symptomatic or asymptomatic) one week after the second dose, which was not statistically significantly different from the Israeli findings.

Efficacy of One Dose

The SIREN study also found that the vaccine was 76% efficacious 21 days after the first dose. This estimate is higher than that provided by a similar study in Israel, which found that one dose was 57% efficacious in preventing symptomatic COVID-19 from 14-20 days after the first dose, although the results are not statistically significant. Nonetheless, these findings suggest that while two doses are needed for maximum protection, even one dose provides some amount of protection against COVID-19.

Efficacy in Preventing Transmission

We do not have absolute, definitive data on the effects of the Pfizer/BioNTech vaccine on transmission dynamics at this time. Nonetheless, we do have some amount of data that suggests the vaccine will reduce spread of the virus. First, as mentioned above, several studies have now found that the Pfizer/BioNTech vaccine reduces infections rather than just symptoms; in particular, the vaccine is able to prevent a large proportion of asymptomatic infections. In addition, recent data out of Israel, published in Nature Medicine, found that one dose of the vaccine was able to drastically reduce the viral load for those infections that did occur. Together, these results all suggest that the Pfizer/BioNTech vaccine can drastically reduce the risk of both symptomatic and asymptomatic infection, potentially/likely reducing transmission after the same as well.

Efficacy Against Variants

Some limited amount of data has emerged about the efficacy of the Pfizer/BioNTech vaccine against different variants of COVID-19. This data has, at times, been somewhat muddled and contradictory, in no small part because the lab studies on the topic have often used different methods to make their assessments, not all of which are as useful as others. However, in general, some broad statements can be made. First, as a recent Nature Medicine study noted, it is likely that the neutralizing titers of serum from vaccinated individuals will be lower against the B.1.1.7, P.1, and especially the B.1.351 variants of the virus (UK, Brazil, and South African variants, respectively).

However, it is important to maintain context on what lower titers actually mean; all it means is that there is less of the neutralizing antibody in the blood. That does not mean that there is not enough neutralizing antibody to still successfully suppress the virus. The gold standard for determining whether the neutralizing antibodies are able to stop the virus from infecting cells is the plaque reduction neutralization test (PRNT), which measures whether the serum is able to prevent cell death after exposure to the virus. In a recent study to this effect, it was found that serum from individuals vaccinated with the Pfizer/BioNTech vaccine was able to robustly neutralize all of the tested variants of the virus, including the B1.1.7, P.1, and B.1.351 variants of the virus.

Finally, it is important to remember that antibody neutralization is not the same thing as vaccine immunity; there are many components of the immune response beyond antibody neutralization, and a poor antibody response does not preclude immunity against COVID-19.

Outside of lab data, the B.1.1.7 strain remain most prevalent in the United Kingdom and Israel, where many of the above efficacy studies appear to show high efficacy. In addition, though underpowered, the South African arm of the Pfizer trial showed 100% efficacy of the vaccine against severe infection which, in the context of the lab studies, strongly suggests the vaccine maintains significant efficacy against the B.1.351 variant.

Moderna

In late 2020, clinical trial data (later published in the NEJM) showed that the Moderna vaccine was roughly 94% efficacious in preventing symptomatic COVID-19, with 100% efficacy against hospitalization and death. On the basis of this data, the Moderna vaccine was authorized in many jurisdictions and has since been distributed to large numbers of individuals. Due to the more limited supply of the Moderna vaccine than the Pfizer/BioNTech worldwide, the Moderna vaccine has not had as many large, nationwide studies specifically aimed at determining efficacy of the vaccine for symptomatic and asymptomatic infection, though it is highly likely that given their highly similar mechanisms of action, properties found of the Pfizer/BioNTech vaccine will likely hold for the Moderna vaccine. However, these studies are ongoing, as are clinical trials to test the vaccine in pediatric populations and to identify boosters against variants.

Johnson & Johnson/Janssen

In January 2021, Johnson & Johnson/Janssen (hereafter abbreviated as J&J) announced that their Phase 3 trial found that their one-dose vaccine was 66% effective in preventing moderate to severe COVID-19, with 85% efficacy against preventing clinically severe COVID-19 and no deaths in the vaccinated group due to COVID-19. On the basis of these data, the vaccine was granted Emergency Use Authorization in many jurisdictions around the world and has since been rolled out to millions of people.

This is, as noted above, a one-dose vaccine regimen at present. Studies on the efficacy of a two-dose regimen are currently ongoing, as are studies on the ability of the vaccine to prevent transmission of COVID-19.

Efficacy Against Variants

The J&J trial was run around the world, allowing for assessment of the efficacy of the vaccine against different variants prevalent at different regions. Overall, the vaccine had an efficacy of 66%, but this varied across regions. In the United States, the J&J vaccine had an efficacy of roughly 72%, whereas in South Africa (where the B.1.351 variant is predominant), the vaccine had an efficacy of 64% in preventing moderate to severe COVID-19. The vaccine had roughly 68% efficacy against moderate to severe disease in Brazil, where the P.1 and P.2 variants are prevalent. Nonetheless, across the world, the vaccine remained highly effective at preventing hospitalization and death. Trials are ongoing to determine if specific boosters against variants will improve efficacy of the vaccine.

Novavax

In March 2021, Novavax reported that their Phase 3 trial had reached its final analysis, showing that their vaccine was roughly 96% efficacious in preventing COVID-19 in the United Kingdom. However, this vaccine appeared significantly affected by the South African variant of COVID-19; in the South African arm of the trial, it was found to have an efficacy of roughly 55% in HIV-negative individuals. Nonetheless, the vaccine was highly effective in preventing severe disease, even in South Africa. Continued studies are ongoing to determine the efficacy of the vaccine against different variants. This vaccine candidate is currently not yet authorized in most jurisdictions.

Who should get a COVID-19 vaccine?

The following sections will go through the CDC guidelines and recommendations for vaccination. Depending on your jurisdiction, other regulatory agencies may have slightly different recommendations. This is not to be construed as medical advice; it is strictly a discussion of the CDC guidelines. If you have questions about your medical conditions and whether it poses a contraindication to vaccination, please speak with your physician.

It is currently recommended that the COVID-19 vaccine be given to all people above the age of 16 that do not have medical conditions that prevent them from being vaccinated. Some regulators have subdivided different vaccines as being used for different populations; for example, the AstraZeneca vaccine, in some jurisdiction, is preferentially used for elderly populations, whereas the Pfizer vaccine is the only vaccine used for individuals between 16 and 18 years of age. However, in general, unless there is a medical contraindication to vaccination, all individuals are medically eligible to be vaccinated!

Contraindications and Precautions to Vaccination

Per the CDC guidelines, the only absolute contraindications to vaccination with a COVID-19 vaccine are a known and documented history of severe and/or immediate allergic reaction to a previous dose of the vaccine or a component of the vaccine. In addition, individuals with a history of immediate allergic reaction to any vaccine or injection are considered to have a precaution to vaccination. Both these groups of individuals should consult with an allergist-immunologist to discuss vaccination strategies prior to receiving a COVID-19 vaccine.

The COVID-19 vaccines do not have latex, eggs, or gelatin. As such, the CDC does not consider allergies to these substances to be contraindications or precautions to COVID-19 vaccines. Similarly, the CDC does not consider allergies to other oral drugs or environmental factors to be contraindications or precautions to vaccination.

Because individuals in the clinical trials received no other vaccinations within 14 days of COVID-19 vaccination (including the influenza vaccine), there is only limited data on coadministration with other vaccines. As such, it is currently recommended that the COVID-19 vaccine not be administered within 2 weeks of another vaccine.

Recommendations for Individuals with Past COVID-19 or Exposure to COVID-19

The clinical trials showed that individuals with past COVID-19 infection still received the vaccine safely and efficaciously. As such, past COVID-19 is not a medical contraindication or precaution to vaccination. However, while vaccine supplies are still limited, it is recommended that individuals that have been diagnosed with COVID-19 AND received monoclonal antibody treatment in the previous 90 days defer their vaccination until at least 90 days have passed due to the low risk of reinfection during that timeframe.

Individuals that have had a confirmed exposure to COVID-19 should not go into the community to get a vaccine until their quarantine has ended to prevent transmission of the virus. However, if the patient is in a congregate setting where healthcare services can be provided without exposing the community or healthcare workers, the patient can receive the COVID-19 vaccine.

Individuals with Chronic Conditions

The clinical trials included individuals with a wide range of common chronic conditions; conditions such as hypertension, diabetes, coronary artery disease, obesity, asthma, COPD, etc., are not contraindications to vaccination for COVID-19 -- and indeed, individuals with these conditions are at higher risk of severe COVID-19 and should be vaccinated.

HIV and other immunocompromising conditions are not contraindications to vaccination because the COVID-19 vaccines are not live vaccines, meaning that they should not pose a particular safety risk to immunocompromised individuals. The clinical trials included individuals with HIV and found that the vaccine was still efficacious, though often somewhat less than for individuals without HIV, and was still safe. Immunocompromised individuals should speak with their treating physician to discuss the optimal timing of receiving the vaccines, particularly if they are on immunomodulatory medication.

There is currently no evidence suggesting that autoimmune conditions, Guillain-Barre Syndrome (GBS), or Bell's palsy are associated with the COVID-19 vaccines. As such, the CDC states that a history of these conditions is not a contraindication to vaccination; individuals with autoimmune conditions, GBS, or Bell's palsy can receive the COVID-19 vaccines unless they have a separate contraindication.

Finally, there were some reports that individuals with a history of injectable dermal filler usage experienced rare instances of swelling near the filler site after receiving an mRNA vaccine (i.e. Pfizer/BioNTech or Moderna). These cases are relatively rare and are easily treated without serious complications. As such, the CDC recommends that a history of dermal filler injection is not a contraindication to vaccination, but if swelling is observed at filler sites after the vaccine, that the patient should contact their physician.

Pregnant and Lactating Individuals

There is no evidence or reason to suggest that the COVID-19 vaccines pose a safety risk to the mother or the child when administered to pregnant or lactating individuals, particularly after the vaccination of hundreds of millions of individuals around the world. In addition, pregnant women are at higher risk of severe COVID-19 infection, with an increased risk of poor outcomes to both the mother and the child.

As such, though the clinical trials did not explicitly test the vaccine in pregnant women, based on the safety data and vaccination experience to date, the CDC recommends that pregnant women be eligible for the COVID-19 vaccine. This is a view shared by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.

Similarly, there is no reason to believe that the vaccine will pose a risk in lactating women, so they are also eligible to receive the COVID-19 vaccine.

What side effects should I expect after vaccination, and when should I seek medical care?

Side effects of the COVID-19 vaccine can include pain, redness, and swelling at the injection site. In addition, you may experience fatigue, muscle and joint pains, fever, chills, nausea, headaches, sweating, swollen lymph nodes, or other flu-like symptoms. These are a sign that the body is generating an immune response and is developing protective immunity.

The CDC recommends that you call a doctor if:

• Your arm pain, redness, or swelling continues to worsen more than 24 hours after you received the vaccine, or
• Your symptoms do not resolve within a few days, or
• If you are worried about your symptoms for any other reason.

Severe allergic reactions to the COVID-19 vaccine, such as anaphylaxis, are very rare, especially more than 15 minutes after the vaccine. However, if you believe you are having a severe allergic reaction or other sever reaction, it is recommended that you should seek emergency medical care. Symptoms of anaphylaxis include:

• Throat tightening, difficulty breathing
• Nausea/vomiting, diarrhea, abdominal pain
• Dizziness, fainting, palpitations, flushing, pallor
• Hives, redness, itchiness, immediate and marked swelling
• Agitation, confusion

This condition is quite rare and is easily treatable with prompt medical attention. Virtually all cases of anaphylaxis will present immediately, within 15 minutes of vaccination. However, being mindful of these symptoms is nonetheless wise.

What are the current guidelines on NSAID use before and after vaccination?

Per CDC guidelines, it is not recommended that you stop taking any medications that you are currently on without first consulting with your physician. If you are taking NSAIDs daily for management of a chronic medical condition, you should not stop taking them before the COVID-19 vaccine without asking your physician.

The CDC recommends not taking additional medications beyond your daily medication regimen, including NSAIDs or acetaminophen (Tylenol), before getting the COVID-19 vaccine.

After getting the COVID-19 vaccine, the CDC does not have specific data or recommendations on whether NSAIDs or acetaminophen will reduce efficacy of the vaccine. However, the participants in the clinical trials for the vaccines were not told to avoid NSAIDs or acetaminophen after the vaccine, and there is not evidence suggesting that the vaccine was less efficacious in individuals that did take these medications. As such, unless you have a specific medical condition that prevents you from taking these drugs, most institutions recommend NSAIDs or acetaminophen for relief of side effects after receiving the COVID-19 vaccine.

What are the current guidelines on alcohol or marijuana use before and after vaccination?

The participants in the clinical trials were not instructed to avoid alcohol or marijuana after the vaccine, and there is not specific data that would suggest it impacts vaccine efficacy. However, it is important to keep in mind that both alcohol and marijuana carry health risks of their own, and using these drugs or others can exacerbate side effects from the vaccine, which can unnecessarily delay recovery.

Is there a relationship between vaccine side effects and protection from COVID-19?

Individuals in the clinical trials that reported few-to-no side effects were still protected with more than 90% efficacy, as were individuals that reported significant side effects from the COVID-19 vaccines. As such, there is no reason to believe that there is any significant relationship between the vaccine side effects and the protection conferred by the vaccine.

Would emergence of a vaccine-resistant variant require full clinical trials for an updated vaccine?

Though not all regulatory bodies or jurisdictions have made firm indications, the US FDA has indicated that minor updates to approved vaccines to cover future variants of SARS-CoV-2 would not need to undergo a separate three-phase trial; rather, an expedited immunogenicity trial can be conducted to verify that the vaccine produces an immune response against the variant of the virus, and the vaccine could be quickly authorized and distributed as an amendment to the previous authorization or approval.