Frequently Asked Questions and Answers About COVID-19 Vaccines

In this article, Covid-19 vaccines are the topic of a scientific source collection we share: frequently asked questions, published research and comments from academics.

Important note: The scientific data and comments below mainly concern new-generation mRNA and viral vector vaccines, because the FDA (US Food and Drug Administration) has granted “emergency use authorization” only to these 3 COVID-19 vaccines. However, international studies have shown that the inactivated coronavirus vaccine CoronaVac, developed by the Chinese biotechnology company Sinovac and widely administered in Turkey, is also safe and 50-90% effective in protecting against serious Covid-19. Some warnings and information listed below can therefore also be generalized to inactivated coronavirus vaccines. Situations specific to inactivated coronavirus vaccines are identified in the article.

VACCINES – MECHANISM, EFFICACY, SAFETY

How Do mRNA Covid-19 Vaccines (Pfizer / BioNTech and Moderna Covid-19 Vaccines) Work?

One developed by Pfizer / BioNTech (BNT162b2) and the other by Moderna (mRNA-1273) are the two messenger RNA (mRNA) vaccines currently available in many Western countries. Their mRNA carries genetic instructions for making the SARS-CoV-2 “spike” protein (the spikelike projections on the virus's surface).

After the vaccine is injected, the mRNA is taken up by macrophages near the injection site and instructs these cells to make the spike protein. It then appears on the surface of the macrophages, mimicking the way we fight infections and protecting us against SARS-CoV-2 (the novel coronavirus responsible for this pandemic) through an immune response. Enzymes in the body then break down and dispose of the mRNA. There is no live virus in this vaccine, and no genetic material enters the cell nucleus.

Although the BioNTech and Moderna vaccines are the first mRNA vaccines widely tested and used in the community, scientists have worked on mRNA vaccines for years. To prevent mRNA breaking down in the body, developers place it in a lipid nanoparticle as a protective enclosure.

How Do Adenovirus Covid-19 Vaccines (Such as Johnson & Johnson and AstraZeneca) Work?

The J&J vaccine is a recombinant replication-incompetent human adenovirus serotype 26 vector encoding a full-length, stabilized SARS-CoV-2 spike protein antigen. This may be hard to understand, so let us unpack it in words more readily understood by us mortals:

• “Recombinant”—genetically engineered in a laboratory. Yes, I know it can mean more than that, but this is the essence.
• “Replication-incompetent”—unable to multiply in humans. There is no risk of viral spread.
• “Adenovirus serotype 26”—many adenovirus subtypes circulate in the community. Although rare, preexisting immunity to an adenovirus may reduce our response to the vaccine. The J&J vaccine's name refers to this serotype (Ad26) and the antigen it carries: Ad26.COV2.S.
• “Vector encoding”—the virus acts as a carrier (vector) for the gene that makes (encodes) the antigen.
• “Full-length, stabilized SARS-CoV-2 spike protein antigen”—researchers took the genetic machinery, or DNA, from SARS-CoV-2 to create the entire spike antigen and made it stable enough to be carried inside.

When the vaccine is injected, the adenovirus does not multiply in the body, but its genetic material can enter the host cell nucleus and be converted to messenger RNA. This mRNA then produces spike protein antigens from SARS-CoV-2, eliciting a host response similar to natural infection with the virus that causes Covid-19. Both antibody and cellular immunity are stimulated.

If you are more of a graphics-oriented person, here is a useful diagram:

Remember that other adenovirus vector vaccines carrying SARS-CoV-2 spike protein DNA are also in use around the world. The Oxford / AstraZeneca vaccine uses a chimpanzee adenovirus modified so that it cannot multiply in humans. The Sputnik V vaccine starts with the same Ad26 adenovirus as the J&J vaccine, but then switches to adenovirus serotype 5 for the second dose. This switch theoretically improves its booster effect by reducing the likelihood that acquired immunity to Ad26 will diminish the immune response.

How Does the Sinovac Vaccine Work?

In Turkey, the most widely available Chinese vaccine is an inactivated (killed) coronavirus vaccine. Comprehensive (phase-3) clinical trial results for it have still not been published in a scientific journal, but developer Sinovac has made an official statement: the vaccine was reported to provide 50.6% protection according to results from Brazil and 91.2% according to studies in Turkey.

The mechanism of action of inactivated COVID-19 vaccines can be seen below:

What Do We Know About the Efficacy of MRNA Vaccines?

Both mRNA vaccines are highly effective. Tens of thousands enrolled in their large clinical trials, and the mRNA vaccines reduced the likelihood of Covid-19 compared with placebo vaccines by approximately 95%. Sometimes data are so strong that we do not even need to carry out a statistical analysis—that was the case in both of these trials. The results were that good.

We regard randomized, placebo-controlled clinical trials as the strongest form of clinical evidence, but additional details make these results even more compelling. First, the vaccines prevented not just any illness caused by SARS-CoV-2, but also—very importantly— severe Covid-19. Preventing severe disease could turn Covid-19 from a global threat into more of a nuisance like a common cold. Second, although both vaccines are given in two doses, some protection was provided just 10 to 14 days after the first dose.

The efficacy noted after the first dose raised questions about whether we should vaccinate twice as many people with one dose rather than give everyone the full two-dose schedule. However, the 95% vaccine efficacy results come after the second dose, which boosts the immune response and probably makes it more durable. Consequently, administration of 2 doses is recommended.

Overall, these impressive results made the two mRNA vaccines the most effective vaccines to date—much more effective than flu vaccines, at least in the short term. Protection is far better than expected, which is why many of us infectious disease, virology, immunology and public health specialists are positively giddy when asked to discuss their efficacy.

An important caveat about the favorable efficacy results in clinical trials is that vaccine performance—effectiveness—in clinical practice may differ. The good news from the first population-based studies is that these vaccines are also highly effective in settings commonly called the “real world.” For example, symptomatic Covid-19 fell by 94% in the mass vaccination program launched in Israel with the Pfizer vaccine. Moreover, the vaccine worked well when given to nursing-home residents, a population not included in the clinical trials and one that might not be expected to respond to vaccination given their age and numerous underlying conditions. Reports from several institutions also show falling Covid-19 rates among healthcare workers after vaccination

How Were Johnson & Johnson Vaccine Trials Conducted, and How Effective Was the Vaccine?

The J&J vaccine clinical trial began in September 2020. Approximately 40,000 participants were enrolled in North America (the US and Mexico), Latin America (several countries, with most enrolled in Brazil) and South Africa, and volunteers were randomly selected to receive one dose of Ad26.COV2.S or placebo.

The primary endpoint was the occurrence of moderate-to-severe Covid-19 beginning 14 and 28 days after vaccination, defined as a positive molecular test for SARS-CoV-2 and a set of protocol-defined symptoms.

The trial also assessed test results, even in those who had not developed any illness suggesting Covid-19, as a marker of asymptomatic infection, as well as detailed safety and tolerability information.

The vaccine's overall efficacy in reducing moderate-to-severe Covid-19 was 66%-67%. Encouragingly, it was equally effective in those younger and older than 60—importantly, few participants were in the oldest age categories, and those over 60 with additional illnesses did not appear to be so either. Results were more impressive for preventing serious illness, hospitalization and death. The vaccine reduced the risk of severe disease by 85%, hospitalization by 93% on or after day 14 and by 100% on or after day 28; all seven Covid-19-related deaths occurred in the placebo arm.

There were small regional differences in efficacy: the vaccine was 72% effective at preventing moderate-to-severe disease in North America, 66% in Latin America and 57% in South Africa.

A very interesting endpoint in this trial, not yet reported in the Pfizer / BioNTech or Moderna trials, was whether the vaccine prevented asymptomatic seroconversion (illness without symptoms). Presumably, these were people who had SARS-CoV-2 infection but did not feel ill enough to report symptoms to the study sites. After day 29 in the J&J trial, there were 10 asymptomatic seroconversions in the vaccine group and 37 in the placebo arm, a reduction of 74%. Because there is an ongoing concern that protection against disease is not the same as protection against infection—with implications for asymptomatic transmission—these data strongly support the vaccine also reducing transmission risk.

If mRNA Vaccines Are More Effective, Why Should We Use an Adenovirus or Inactivated Coronavirus Vaccine?

It is natural for both doctors and patients to make cross-trial comparisons and note that the J&J trial's overall efficacy was lower than the roughly 95% seen in the Pfizer / BioNTech and Moderna trials. An important caveat is that the studies took place in different contexts. The J&J trial occurred when Covid-19 incidence was much higher, in different countries, and after variants that might be less susceptible to mRNA vaccines had emerged. In addition, data on the critical endpoints of preventing severe disease, hospitalization and death look very strong, as do data on activity against variants (a similar situation also applies to Sinovac). Consequently, during this vaccine shortage, we recommend that people receive the vaccine available to them. Additional doses—boosters with the same or other vaccines—may be needed and recommended in the future. Whether this will apply only to the J&J vaccine or to all vaccines is currently unknown.

How Long Will Vaccine Effects Last? Are Booster Doses Necessary?

Because mRNA vaccines have been tested only since summer 2020, we lack information on the durability or duration of protection. Data from the Moderna vaccine's phase 1 trial showed neutralizing antibodies persisting for about 4 months, although titers declined somewhat over time. With no information about how long vaccines will protect, there is currently no specific recommendation for booster doses. However, both companies are developing vaccines that can be given as boosters and also cover new SARS-CoV-2 variants less susceptible to vaccine suppression.

As with mRNA vaccines, the durability of Johnson & Johnson vaccine protection is unknown. This is particularly relevant to Ad26.COV2.S, because the clinical trial strategy used only one dose and that is how it was given under the initial emergency use authorization. An ongoing trial called COV3009 is testing this same vaccine with a booster given 8 weeks after the first, with results expected at the end of 2021.

Do Vaccines Work Against Emerging SARS-CoV-2 Variants?

Currently, information on how effective mRNA vaccines will be against emerging SARS-CoV-2 variants is limited. The Johnson & Johnson vaccine showed roughly the same efficacy in all regions and countries, including South Africa and Brazil. Specifically, the vaccine was 72% effective in the United States, where 95% of cases were descendants of the B.1.351 variant, 68% in Brazil and 64% in South Africa. Both mRNA vaccine trials preceded identification of the major variants now present in many countries. Studies suggest vaccines may protect better against some variants than others. Broad generalizations about vaccine activity against variants therefore cannot be made. The US Centers for Disease Control and Prevention (US-CDC), regarding circulating variants, whether each variant reduces neutralization using convalescent and postvaccination sera. An important limitation of these studies is that vaccine protection is more complex than simply measuring antibody responses.

From a practical perspective, discovering these variants does not change the basic vaccination recommendations. In particular, people are not advised to wait for a new or modified vaccine in the hope that it will be more effective against emerging SARS-CoV-2 variants. Both Pfizer and Moderna are developing modifications to their existing vaccines designed for broader activity against emerging strains or variants, but when they will be available and how they will be administered are unknown.

Are Chinese Vaccines Effective Against Variants?

Two Chinese biotechnology companies, Sinovac (vaccine CoronaVac) and Sinopharm (vaccine BBIBP-CorV), produced inactivated coronavirus vaccines. Their effects against Covid-19 variants were reported in a paper published as “Correspondence” in NEJM on 6 April 2021. Scientists at the Beijing Institute of Microbiology and Epidemiology in China assessed the neutralizing effects of Sinovac and Sinopharm vaccines against D614G, B.1.1.7 (UK) and B.1.351 (South Africa).

They found that blood samples from patients who had recovered from Covid-19 effectively neutralized D614G and B.1.1.7 (UK), but were “significantly less effective” against B.1.351 (South Africa). This may be one explanation for the intensity of the 3rd wave of cases in Turkey.

Ultimately, molecular sequencing of viruses from Covid-19 cases occurring after vaccination will tell us how well these vaccines work against variants.

The criteria below provide explanatory information about recent mutations or changes in circulating viruses. The levels also help communicate and perceive risk.

Do Vaccines Prevent Transmission to Other People?

Many comments on the original vaccine trial results identify the lack of information on asymptomatic infection as a limitation in our knowledge of efficacy, particularly concerning disease spread. This is indeed a theoretical concern, because up to 40% of people infected with SARS-CoV-2 have no symptoms but can still transmit the virus to others.

However, emerging evidence now strongly suggests vaccine recipients are less likely to transmit infection to others. In a large observational study in Israel, vaccinated people had a 90% reduction in asymptomatic infection risk compared with the unvaccinated. People infected after vaccination also have lower viral loads than infected unvaccinated people. Lower viral loads most likely mean less transmission risk. In addition, after day 29 in the Johnson & Johnson trial, there were 10 asymptomatic seroconversions in the vaccine group and 37 in the placebo arm—a 74% reduction (seroconversion is the development of measurable antibodies after a virus enters the body). It is reasonable to assume fewer asymptomatic seroconversions mean fewer opportunities for transmission. These encouraging data remind us that many widely used vaccines strongly protect against both disease and transmission—so much so that infection control is a main motivation behind some vaccination policies.

Remember that although vaccines reduce transmission risk, we cannot say they eliminate it—protection will never be 100%. Consequently, until case counts decline and a larger share of the population is vaccinated, we must continue emphasizing to our patients that vaccination does not allow us to stop other important measures to prevent Covid-19 spread. Wearing masks in public, social distancing and avoiding crowded indoor settings remain important strategies for now.

What Do We Know About Short-Term Vaccine Side Effects and Safety?

All vaccines available under emergency use authorization are very safe—this is good news and should be the dominant message for our patients. Indeed, since their rollout in late 2020 and after millions of doses, no clear pattern of serious or unexpected adverse events has emerged. This is particularly reassuring because the first wave of vaccines went to many frail older people who might be at greater risk of side effects. But no vaccine—indeed, nothing in medicine—is 100% safe.

Before discussing side effects, we must acknowledge that Covid-19 vaccine safety will remain in the spotlight for some time: these are new vaccines for a new disease. Rare events will make news, increasing attention and concern out of proportion to the actual risk. Our task will be to put these rare events in perspective and underline that these risks are much lower than the risk of becoming ill with Covid-19.

mRNA vaccines are classified as “reactogenic,” meaning they will cause some side effects in most recipients, reflecting the vigorous immune response they produce. In clinical practice, we should put them 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, particularly 12 to 24 hours after administration. Approximately 1% of trial participants classified the pain as “severe.” Fatigue and headache are other relatively common side effects; high fever is less common. These effects generally resolve within a few days and respond to acetaminophen (paracetamol, parol) or a nonsteroidal anti-inflammatory drug such as ibuprofen. Overall, side effects are more common in younger than older recipients, and the second shot causes more side effects than the first.

Some Moderna vaccine recipients develop redness, warmth and itching at or near the injection site, which may have a delayed onset (typically 5 to 14 days after the shot). Regional adenopathy (especially enlarged lymph nodes in the armpit) is also possible. Symptoms last several days, are not a contraindication to the second shot, and most people do not have this reaction again. Some have been treated with oral antihistamines and topical steroids.

In the mRNA vaccine trials, facial (Bell) palsy was reported more often among vaccine recipients than controls, but there were too few cases to conclude that this exceeded what would naturally occur by chance in groups of this size. There were no cases of Guillain-Barré syndrome or transverse myelitis.

Although hypersensitivity occurred equally in placebo and vaccine groups in both mRNA trials, after vaccine distribution in the UK and United States, reports emerged of recipients experiencing severe allergic reactions (anaphylaxis) shortly after their first dose. The current leading suspect is polyethylene glycol, a compound present in both vaccines. Because of these rare events, administration includes a 15-minute observation period after vaccination—30 minutes for anyone with a history of any type of severe allergic reaction.

It is critical to emphasize that these allergic reactions are rare: the current estimate is anaphylaxis in approximately 2 to 5 people per million vaccinated. Although these severe-allergy rates exceed those with other vaccines, they are considerably lower than the rate reported with penicillin, estimated at 1 in 10,000. Because severe penicillin allergies do not make news, our task is to put this risk in context.

In the Johnson & Johnson trial, common solicited vaccine-associated adverse reactions included injection-site pain (48.6%), headache (38.9%), fatigue (38.2%) and myalgia (33.2%). Most were mild to moderate and lasted a median of 1-2 days. Side effects were more common in participants younger than 60. Compared with MRNA vaccines, these reported effects are somewhat less common. No anaphylaxis occurred among approximately 20,000 vaccine recipients in the trial. Indeed, US-CDC has issued guidance that people who experienced anaphylaxis with the first Pfizer / BioNTech or Moderna dose may receive the J&J vaccine 4 weeks later under close observation.

Serious adverse effects in the J&J trial were uncommon and similar between study arms (0.4% with vaccine and placebo). Although numbers were small, some important effects were more common with vaccine than placebo: urticaria (5 vaccine, 1 placebo), thromboembolic events (15 vaccine, 10 placebo) and tinnitus (6 vaccine, 0 placebo). Given their rarity, determining whether they are vaccine-related awaits wider use and further data collection.

The first phase of people receiving these vaccines included older people, many with other medical problems or living in nursing homes or both, and some died after vaccination. However, by 23 March 2021, more than 156 million doses had been administered. Every death after vaccination was reviewed by US-CDC and FDA physicians, including medical records, death certificates and autopsy reports where available, and no link with vaccination has so far been identified.

What Do We Know About Long-Term Vaccine Side Effects and Safety?

Covid-19 vaccines were developed extraordinarily quickly; under normal circumstances, a vaccine is developed within months, within years (both mRNA trials began in summer 2020 and the J&J trial in September 2020). With other vaccinations, however, severe reactions typically occur within days or weeks of administration. Fortunately, long-term vaccine side effects are quite rare, and hypothetical associations have subsequently been refuted by carefully conducted population-based studies.

More vaccine safety data will be reported to the Vaccine Adverse Event Reporting System (VAERS). This program is an existing national early-warning system established to identify possible safety problems with any licensed vaccine and has operated since 1990

VACCINATION – WHICH PATIENTS

Are Recommendations the Same for Each Available Vaccine?

Broadly, recommendations for the two mRNA vaccines are quite similar: each is two-stage and they can mostly be given to similar populations.

However, despite similar mechanisms of action, safety and efficacy, the two mRNA vaccines differ in important ways. As widely publicized, both require special attention to maintaining extremely low temperatures during distribution, with Pfizer / BioNTech having particularly strict cold-storage requirements. Indeed, its −70 ° C shipping and storage requirement suggests it would be unsuitable where ultra-cold freezers are unavailable. Since the original rollout, however, Pfizer has submitted data to FDA showing stability between -25 ° and -15 ° C for up to 2 weeks, offering greater shipping and storage flexibility. It must be used within 5 days of thawing. The Moderna vaccine can be shipped at −20 ° C and is stable for 30 days at refrigerator temperature.

These differences have little effect on doctors unless they are involved in obtaining or distributing vaccines. For those caring for patients, more important is that Pfizer / BioNTech is authorized for age 16 and Moderna for ≥18 years. Both are being studied in children, but at this point should not be given to children.

Both mRNA vaccines require 2 doses for a complete series: Pfizer / BioNTech is given every 21 days and Moderna every 28 days. If a patient misses this second-dose interval, no interval between the doses invalidates the first dose for either vaccine. In other words, there is no need to restart; give the second dose as soon as possible after the 21- or 28-day target. It is possible to schedule a second dose up to 6 weeks after the first.

Johnson & Johnson differs from mRNA vaccines in several important ways. Based on small studies during development showing promising immune responses after a single shot, the trial leading to authorization used a single-dose approach. An ongoing trial called COV3009 is testing this same vaccine with a booster 8 weeks after the first, and results are expected later this year (the other two widely used adenovirus vector vaccines use two doses).

Unlike mRNA vaccines, J&J has less restrictive cold-storage requirements. It can be stored at normal refrigerator temperatures (2–8 ° C) for 3 months and has a 2-year shelf life when frozen. These features make it easier to ship and distribute than mRNA vaccines.

Can One Vaccine Be Preferred Over Another for Particular Patients?

Pfizer / BioNTech is authorized for age 16, and Moderna and Johnson & Johnson for ≥18 years. Apart from this age difference, no target population is better suited to one vaccine or another. During limited supply, we should advise eligible patients to receive the vaccine offered to them. People are already commonly asking others which vaccine they received, but reassuringly, all three were highly protective against severe Covid-19 in their clinical trials.

Once an mRNA series begins, it should be completed with the same vaccine on the recommended schedule if possible. There are no safety or efficacy data on using one vaccine for the first dose and a different one for the second. However, US-CDC now states that when the first product cannot be identified or is no longer available, any available mRNA Covid-19 vaccine may be given to complete the series with a minimum interval of 28 days. Although this strategy should be avoided if possible, I cannot think of a reason it would be problematic under these exceptional circumstances.

For patients with a severe allergic reaction to their first mRNA dose, US-CDC now recommends J&J as a second dose under close observation.

Are There Contraindications to Any of the Vaccines?

The only absolute contraindication is known hypersensitivity to vaccine components. Specific CDC recommendations list the following:

• Severe allergic reaction (such as anaphylaxis) after a previous dose of an mRNA Covid-19 vaccine or any of its components
• An immediate allergic reaction of any severity to a previous mRNA Covid-19 dose or any of its components (including polyethylene glycol [PEG])

Remember that anaphylaxis in response to another vaccine or injectable therapy is not a contraindication to these Covid-19 vaccines, but people with this history should be observed for at least 30 minutes after their dose.

If a person experiences anaphylaxis or another severe allergic reaction to the first mRNA dose, they should not receive the second. However, CDC says they should consider Johnson & Johnson 4 weeks later under close observation.

People with severe pain or other nonallergic reactions to the first mRNA dose will need an individual decision about proceeding with the second—it is not contraindicated, but side effects may be worse with the second dose (in people with a Covid-19 history, the first causes more side effects than the second, probably because their immune systems are “primed” to respond to a Covid-19 vaccine). For people concerned about severe effects recurring after the second dose, a potential strategy should be used: acetaminophen or ibuprofen as soon as pain starts after that dose. US-CDC does not recommend giving these drugs before vaccination because they could theoretically blunt vaccine-induced antibody responses.

Monoclonal antibodies or convalescent plasma used to treat Covid-19 may potentially reduce vaccine efficacy. Anyone receiving them should postpone a Covid-19 vaccine for at least 90 days, an interval influenced both by their known half-life and by the likelihood that someone with Covid-19 would experience reinfection during that period.

Can a Patient With a History of Allergic Reactions Receive a Covid-19 Vaccine?

Someone with an allergy history can certainly be vaccinated, whether the allergy is to another vaccine, medication, bee stings, food or pollen. However, they should be observed for 30 minutes after vaccination rather than the usual 15.

As widely reported, rare severe allergic reactions have occurred after the first mRNA dose. When this occurs, a second dose of either mRNA vaccine should not be given. US-CDC currently states that a single Johnson & Johnson vaccine may be considered at a minimum interval of 28 days after the first mRNA dose.

No anaphylaxis occurred among approximately 20,000 J&J trial vaccine recipients. Importantly, this rare but potentially life-threatening reaction to mRNA vaccines became apparent only after hundreds of thousands were vaccinated following emergency authorization. Consequently, we do not yet know whether Ad26.COV2.S will also rarely cause it.

Should Immunocompromised Patients Be Vaccinated, and How Should We Manage Their Medications?

US-CDC considers immunocompromised patients at high risk for severe Covid-19. These are broadly defined as people with histories meeting the following criteria, which are not 100% inclusive:

• Cancer
• Bone marrow transplant
• Solid organ transplant
• Stem cells for cancer treatment
• Genetic immune deficiencies
• HIV
• Use of oral or intravenous corticosteroids or other drugs called immunosuppressants that reduce the body's ability to fight certain infections (for example, mycophenolate, sirolimus, cyclosporine, tacrolimus, etanercept and rituximab)

Because of their increased risk of severe Covid-19, these individuals should receive Covid-19 vaccines unless contraindicated. That is the easy part.

More difficult is predicting safety and especially efficacy in this population, because the trials did not include large numbers in these individual categories. Pfizer / BioNTech and Moderna contain no live virus, so there is no risk of viral spread. Whether vaccine antigens might trigger increased rejection risk in transplant patients or autoimmune disease in people with rheumatological or other autoimmune conditions is unknown, but the rarity of such effects with other vaccines is reassuring. The trials also saw no difference in autoimmune or inflammatory conditions between vaccinated participants and placebo. Although we generally do not recommend live-virus vaccines for immunodeficient people, the adenovirus in Johnson & Johnson and other vaccines using this mechanism is modified so vectors cannot replicate in humans. They therefore pose no risk of spreading in immunocompromised patients or transmitting to immunocompromised people at home or elsewhere.

Vaccine efficacy depends on a robust immune response in the recipient; consequently, immunization may be less effective in immunocompromised hosts than in the general population. Blunted antibody responses to Covid-19 vaccination have been reported in solid organ transplant recipients. Further studies of Covid-19 vaccines in people with immunosuppression are ongoing.

The importance of the host's immune response in determining vaccine effectiveness is the basis for the CDC's recommendation that vaccination should ideally be completed at least 2 weeks before immunosuppressive treatments begin. Whether or not this strategy is possible, when immunizing immunocompromised patients against Covid-19, we should inform them about a potential reduction in vaccine effectiveness. This is also a good time to remind them of the continuing importance of other prevention measures, such as wearing masks, social distancing, avoiding crowds, and washing hands. Household members of immunocompromised people should also be vaccinated if possible.

Physicians may wonder about delaying or stopping immunosuppressive treatments or chemotherapy before starting the Covid-19 vaccine series, and then resuming them after both vaccinations have been administered. Although such strategies have theoretical appeal, no general guidance that applies to everyone in this diverse group can currently be given. The American College of Rheumatology published clinical guidance on managing immunosuppression in patients with rheumatic disease on 8 February 2021; it acknowledges the existing uncertainties but offers some general recommendations. Since many patients with other disease conditions also receive immunosuppressive treatments, we will need to consider continuing or delaying immunosuppression on a case-by-case basis, depending on the severity of the underlying condition and the urgency of its treatment.

All clinical trials included small numbers of clinically stable people with HIV receiving antiretroviral therapy — 120 and 176 in the Pfizer / BioNTech and Moderna trials, respectively, and 2.8% of J&J study participants. Although these numbers are too small to draw any conclusions about safety and effectiveness in people with HIV, there is no theoretical reason for someone with well-controlled HIV to have problems with these vaccines, and vaccination is recommended. For people with HIV who are not receiving antiretroviral therapy, especially those with low CD4 cell counts, my opinion is that prioritizing HIV treatment over Covid-19 vaccination is necessary both to prevent HIV-related complications and to improve responsiveness to the vaccine.

Adenovirus vector vaccines contain live virus — are they safe for immunocompromised patients?

Although we generally do not recommend live virus vaccines for people with immunodeficiency, the adenovirus in the Johnson & Johnson vaccine and other vaccines using this mechanism has been modified so that the vectors cannot replicate in humans. As a result, the vaccines pose no risk of spreading to immunocompromised patients or being transmitted to immunocompromised people in households or other settings. (Last review / update 29 March 2021)

What are the concerns about adenovirus vaccines and HIV?

As in the Moderna and Pfizer / BioNTech studies, a small proportion (2.8%) of the people enrolled in the Johnson & Johnson study had stable HIV disease — they were receiving HIV treatment and had no active infection or malignancy. The numbers are too small to say definitively whether the vaccine is more or less effective in this population, or whether there are specific safety concerns, but there is no theoretical reason that there should be.

There are some lingering concerns about adenovirus vector vaccines for people without HIV who are at high risk of acquiring the infection. This is based on the results of a clinical trial called the STEP study, which tested an adenovirus vector vaccine for HIV prevention. It showed that vaccine recipients had a higher risk of acquiring HIV than the placebo group. As a result, some experts have recommended caution about using adenovirus vector vaccines in HIV-negative people at high risk of HIV acquisition.

Should pregnant or breastfeeding individuals be vaccinated?

Although pregnant and breastfeeding individuals were not enrolled in the original Covid-19 vaccine trials, resulting in limited safety data, US-CDC advises that vaccines may be offered to pregnant or breastfeeding people and that they may choose to be vaccinated. This view is shared by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. It is good that all these groups agree! Results of a new Pfizer / BioNTech vaccine trial in pregnant individuals were recently published, and it was found to be both safe and effective.

As in the phase 3 mRNA vaccine studies, pregnant and breastfeeding women could not enroll in the Johnson & Johnson clinical trial, and they were ineligible if they planned to become pregnant soon after enrollment. During the study, eight women became pregnant, four in each study arm (vaccine and placebo), and there were small numbers of adverse pregnancy-related outcomes in both groups — too few to attribute to study participation or the vaccines. A study of the J&J vaccine specifically for pregnant women is being planned.

Importantly, there is no theoretical reason for mRNA or adenovirus vaccines to harm a mother, a developing fetus, or a breastfeeding infant during pregnancy. It is also reassuring that pregnant rats receiving the Moderna vaccine showed no safety concerns related to fetal or embryonic development. If pregnant patients are offered the J&J vaccine, they should be informed about the reassuring experience with the existing Ebola vaccine — another adenovirus vector vaccine. It has been given to approximately 200,000 people without any signal of adverse pregnancy-related outcomes.

A potential benefit of vaccination during pregnancy is the transplacental transfer of maternal antibodies to the baby. This is the main rationale behind the recommendation for pertussis vaccination during pregnancy. A recent case report showed that this antibody transfer also occurs with Covid-19 vaccination; theoretically, it could also provide neonatal protection.

Pregnant individuals should be informed that observational studies show pregnancy to be a risk factor for serious illness due to Covid-19 as well as for influenza (flu)This is Turkey’. Based on this information and their likelihood of exposure to Covid-19, together with information about the limited safety data available to date, pregnant individuals can make an informed decision about whether to accept the vaccine. However, it is important to emphasize that the vaccine should be offered to them, as we do with the influenza vaccine, and that they should be given a chance to have their questions answered. An emergency department doctor or nurse may choose to receive the vaccine, while someone working from home with very little social interaction may choose not to be vaccinated while waiting for more data.

Should vaccination be postponed if a patient has any symptoms or is actively ill?

In people with an acute illness, vaccination should preferably be postponed until they have recovered. This applies to both non-Covid-19 acute illness and acute illness potentially related to Covid-19. However, people with chronic illnesses and stable symptoms are eligible to receive the vaccine; examples might include people with cancer, chronic obstructive pulmonary disease (KOAH) and shortness of breath on exertion, or inflammatory bowel disease and gastrointestinal symptoms. Most participants in the phase 3 clinical trials had underlying medical problems, and although they were not acutely ill, some probably had symptoms from their diseases — that is the nature of chronic medical conditions.

Is there a minimum or maximum age for patients to receive the vaccines?

The Pfizer / BioNTech vaccine is authorized for patients aged 16 and older, and the Moderna and Johnson & Johnson vaccines for those aged ≥18. Studies in children are ongoing, but at this point none of the vaccines should be given to children. There is no maximum age limit. Given the disproportionate toll that Covid-19 has taken on older people — essentially every study identifies advanced age as a risk factor for severe disease — vaccination of older people should be strongly encouraged.

An important unknown based solely on clinical trial results is how effective the vaccines will be in the frail elderly population, especially those of extremely advanced age or those living in nursing homes. Although this is a target population for early vaccination, this particular subset of older people did not participate in the phase 3 clinical trials because study participants had to be ambulatory and clinically stable. However, since the vaccines were introduced, we now have population-based studies, including data from nursing homes, showing a significant reduction in hospitalizations due to Covid-19 among people over 70. These encouraging data suggest that although vaccinated older people have lower antibody levels than younger recipients, they still experience substantial protection.

What is the best way to approach vaccine hesitancy in my patients?

Public skepticism about vaccine safety and effectiveness has a long history, dating back to the earliest efforts to reduce the severity of smallpox in the early 18th century. More recently, widely publicized concerns about the KKK (measles, mumps, rubella) vaccine and an alleged observation linking it to autism, based on a retracted paper, persist to this day despite being consistently discredited in subsequent population-based studies. Other arguments against vaccination include fear of introducing "toxins" into the body, concerns about overwhelming the immune system, a desire for "natural" immunity, and conspiracy theories involving the government or the pharmaceutical industry, or both.

Because the origins of vaccine hesitancy are so diverse, a "one-size-fits-all" approach is not best for every patient. Experts in this field consistently comment that it is important to elicit specific concerns and try to address them without confrontation. Providing reliable information to help fill gaps in understanding about vaccines or the disease is certainly important, but may not be enough to overcome vaccine hesitancy. Many physicians will relate their own and their colleagues' decisions to be vaccinated — and to vaccinate their families — and anecdotally, such a strategy is persuasive in individual cases.

Fortunately, US-CDC has collected clear, patient-facing materials about Covid-19 vaccination in a communication toolkit. This includes simple graphics, videos, and examples of social media posts supporting vaccination.

What advice should be given to patients who believe it is better to wait for "herd immunity" without vaccination?

There are two excellent reasons to recommend vaccination rather than herd immunity. The first is that immunization protects the individual against Covid-19, a potentially life-threatening disease. Although carefully conducted studies show that Covid-19 has a much higher case fatality rate than influenza, and advanced age is the leading risk factor for severe disease, young people can also become seriously ill. In addition, some people with moderately severe illness that does not require hospitalization have significant symptoms that can persist for weeks or months. Common complaints include fatigue, shortness of breath, palpitations, chest pain, difficulty concentrating, and "brain fog."

The second reason to advocate for a person to receive a Covid-19 vaccine is that it will protect others. Patients with Covid-19, the actual disease, are highly contagious early in their illness and can easily transmit the infection to others. In contrast, vaccination is very likely to reduce the risk of viral transmission. So, although we cannot conclude that vaccination eliminates this risk — which is why we still recommend masks and social distancing while case numbers are high — scientific evidence strongly suggests that vaccines make us all safer by reducing vaccines.

VACCINE ADMINISTRATION — MONITORING, PATIENT INSTRUCTIONS

What should be available for emergencies where vaccines are administered?

The key point is to have resources available to manage anaphylaxis — both human resources (for example, nurses, pharmacists, or physicians) and equipment. The CDC lists emergency supplies and equipment that should be available at all sites (such as a pulse oximeter, oxygen, IV fluids, an intubation kit, epinephrine, H1 antihistamines, blood pressure monitors, and stethoscopes). In addition, they state that at least 3 doses of epinephrine should always be available.

Because Covid-19 can also spread from people without symptoms, it is important to ensure that both the person administering the vaccine and the recipient follow the best infection prevention practices during vaccination. These practices include wearing masks, minimizing time in close contact with others, and avoiding crowds in indoor spaces where breathing is poor. The CDC provides guidance on safe practices for immunization during the Covid-19 pandemic.

How should initial side effects be managed?

Analgesics and antipyretics such as acetaminophen and ibuprofen are effective for managing post-vaccination side effects such as injection-site pain, myalgias, and fever. However, the CDC does not recommend taking these medicines before vaccination, because they could theoretically blunt vaccine-induced antibody responses.

Because of the low risk of anaphylaxis, vaccination sites need to have strategies available to assess and treat these potentially life-threatening reactions.

Should acetaminophen or nonsteroidal anti-inflammatory drugs be taken before vaccination to prevent post-vaccination symptoms?

Although these medicines can reduce subjective side effects, they could theoretically blunt the immune response and reduce vaccine effectiveness — which is why they are not recommended before vaccination. However, taking them is helpful once side effects begin. Acetaminophen is preferred for pregnant women.

What information should be given to a person after vaccination?

Normally, people are provided with a vaccine information statement (Vaccine Information Statement – VIS) for each vaccine administered, but VIS documents are not yet available for Covid-19 vaccines. They are known to be developed after vaccines receive formal FDA approval. For this reason, people receiving a Covid-19 vaccine should be given a fact sheet indicating that an emergency use authorization (emercency use authorization – EUA) has been granted, instead of a VIS.

The fact sheets should include the following;

• Basic information about Covid-19, symptoms, and matters we should tell the healthcare professional about before vaccination
• Who should or should not be vaccinated
• Details of the vaccine series
• The vaccine's potential and known risks and benefits, including common side effects
• Information about reporting side effects to the vaccine adverse event reporting system (Vaccine Adverse Event Reporting System – VAERS)
• An explanation of what an EUA is and why it was granted
• All available alternatives authorized to prevent Covid-19
• Additional resources

Does a person vaccinated against Covid-19 need to avoid pregnant or immunocompromised people, or people with chronic or acute illnesses?

mRNA vaccines contain no live virus; none of the vaccine components is transferred to anyone else. In addition, in Johnson & Johnson vaccines, the adenovirus has been modified so that it cannot replicate in humans. As a result, there are no restrictions on contact with people in vulnerable groups, such as pregnant or immunocompromised individuals.

What is "V-safe"? Should patients enroll?

After receiving a Covid-19 vaccine, patients have the option to enroll in V-safe. This CDC smartphone-based tool allows people to report side effects through a secure online site, providing automatic check-ins after receiving a Covid-19 vaccine. When a severe or significant side effect is reported, a CDC representative may call the person who submitted the report to obtain more detailed information about what happened. In addition to collecting this information, V-safe will also send reminders about receiving the second vaccine dose.

Although V-safe is optional, people should enroll. We are in the middle of the largest pandemic in more than 100 years, and vaccines are key strategies for bringing this situation under control. Collecting as much information as possible about vaccine safety is critically important for the coming weeks and months.

Is there anything that should be monitored or reported after vaccination? If so, how can I report it?

Expected side effects do not need to be reported unless they are severe enough to prompt hospitalization or a visit to the emergency department. The most common side effect is pain at the injection site, especially within 12 – 24 hours after vaccination. Approximately 1% of vaccine recipients classified the pain as severe. Fatigue and headache are other relatively common side effects; high fever is less common. These side effects generally resolve within a few days and respond to acetaminophen or a nonsteroidal anti-inflammatory drug such as ibuprofen. In general, side effects from the second dose are greater than from the first and are more common in younger than older people.

Physicians must report serious adverse effects through VAERS. This should be done whether or not you think the side effect is related to the vaccine. The FDA defines a serious adverse effect as one or more of the following;

• Loss of life
• A life-threatening adverse event
• Hospitalization or prolongation of an existing hospital stay
• Persistent or significant disability, or significant disruption of normal life functions
• A congenital anomaly or birth defect
• An important medical event that could endanger the person and require medical or surgical intervention
• Multisystem inflammatory syndrome

Given how quickly the vaccines were developed and went through clinical trials, healthcare professionals strongly recommend reporting any clinically important adverse event after vaccination to VAERS, even if it is uncertain whether it is related to the vaccine. For example, if a 75-year-old man with a history of heart disease has a heart attack between his first and second Covid-19 vaccine doses, this should be reported — even if the vaccine did not cause it. Accumulating such data can identify potential associations.

To expand safety data for these new vaccines, it is important for people who experience problems to report them through V-safe to VAERS.

After receiving a Covid-19 vaccine, should any tests be performed to determine whether the vaccine has worked?

People vaccinated against Covid-19 develop antibodies against the SARS-CoV-2 spike protein. However, there is no recommendation for post-vaccination serological testing. This may change in the future. It is important to point out that current antibody tests do not assess anti-spike antibodies — this information should be provided in the antibody test's package insert.

Although there is no recommendation for post-vaccination blood tests to look at spike antibody responses, some people still get tested because they are immunocompromised, for other reasons, or simply out of curiosity. If such tests are negative, it is important to emphasize that this is not clearly correlated with immunological protection, and consequently revaccination is not recommended at this point.

What changes for people after receiving two doses of vaccine against Covid-19?

People are considered protected at least two weeks after receiving their second vaccine dose. Because they are protected against this serious disease, they will want to know what they can now do.

The CDC provides clear guidance on which activities are sufficiently safe for people who have received two vaccine doses. The agency states that the following, in particular, are sufficiently safe for vaccinated people;

• Gathering indoors without masks with people who have received two vaccine doses
• Gathering indoors without masks with unvaccinated people from another household (for example, visiting relatives who live together), provided none of the people is at high risk from Covid-19.
• Not having to be tested after exposure to someone with Covid-19, as long as there are no symptoms (vaccinated individuals living in a group setting who have been exposed to Covid-19 should continue social distancing for 14 days and be tested even if they have no symptoms).

These appropriate and reasonable recommendations will most likely be relaxed if case numbers continue to fall, a higher proportion of the population is vaccinated, and data continue to show that vaccines strongly reduce the likelihood of transmitting infection to others.

Other recommendations for protecting oneself and others have not changed. For example, people who have received two vaccine doses should still continue wearing masks in public, avoiding crowded places, postponing travel, and maintaining social distance, and should be tested if they develop Covid-19 symptoms.

After vaccination, people with severe immunodeficiency — especially those receiving treatments that inhibit B-cell function, such as rituximab — should continue to avoid contact with unvaccinated people. The main reason is that we do not know how well vaccines will work in immunocompromised people.

THE SECOND VACCINE DOSE

Is there a system to ensure that a person receives the second dose of an mRNA vaccine?

At the first vaccination, the person should be provided with a vaccination card containing information about the vaccine received and the scheduled date for the second dose. The second dose should be scheduled as close as possible to the recommended 21 days (for Pzifer/BioNTech) and 28 days (for Moderna) after the first dose. If this date is not possible, it is better to delay the vaccine by a few days than to give it early. If people enroll in the V-safe program, they will receive a text reminder about their second doses.

Can the second dose of an mRNA vaccine be given earlier than 21 days or 28 days?

Vaccinators should not suggest an earlier date than the recommended interval for the second vaccine dose. However, if a person arrives 4 days early for the second dose and will not return, it is better for them to be vaccinated than not. In other words, the second vaccine dose may be given slightly early rather than not at all.

Can the second dose of an mRNA vaccine be given after 21 or 28 days and still be effective?

The purpose of the first mRNA vaccine dose is to "prime" the immune response; the second is to "boost" it. Although most people have received their second doses on time or close to the scheduled date, there is no biological reason that receiving the second dose late would reduce vaccine effectiveness (provided the interval is not too long). In practice, the second dose should be given as soon as possible after the scheduled date has been missed.

On 21 January 2021, the CDC updated its guidance on the interval between vaccine doses, providing additional information about delayed doses. The agency specifically says that when the recommended schedule is not feasible, the second dose may be scheduled for administration up to 6 weeks (42 days) after the first.

Does the second vaccine dose need to be the same mRNA vaccine?

Although the two mRNA vaccines have the same mechanism of action, the vaccines are not identical, and the second dose should be the same as the first. There are no data showing that receiving a different vaccine as the second dose would be unsafe or less effective, but the vaccines were not developed in this way, and such hybrid dosing strategies should be avoided in most cases. The CDC says that in "exceptional situations" — for example, when the vaccinator cannot determine which vaccine a person received the first time — any authorized mRNA Covid-19 vaccine may be administered to complete the series when there is an interval of at least 28 days between doses. For this and other administration errors, the CDC guidance on what measures to take should be consulted.

COVID-19 OR A POSSIBLE COVID-19 CASE

Should a person exposed to Covid-19 be vaccinated to prevent the disease?

There are currently no data to support immediate use of a Covid-19 vaccine in someone known to have been exposed to an active case in order to prevent subsequent disease. Since the incubation period for Covid-19 is approximately 5 days, the vaccine is unlikely to produce an immune response quickly enough to prevent infection. Consequently, people exposed to Covid-19 need to complete their 10-day quarantine before being vaccinated. After a negative PCR result, this period may be reduced to 7 days (the test should be performed on the 5th day after exposure or later).

Some vaccines for other diseases (especially chickenpox) are effective in preventing infection after exposure. This may become a future recommendation for Covid-19 vaccination, but that is not the case at present.

Should people who have recovered from Covid-19 be vaccinated?

Yes, they should receive a Covid-19 vaccine. Some participants in the clinical trials had evidence of previous SARS-CoV-2 infection (positive antibody tests), and the vaccines were safe and effective in this group.

Since reinfection is rare within the first 90 days after recovering from Covid-19, some people may delay vaccination for that long — however, there is no contraindication (a situation in which treatment is unsuitable) if they want to be vaccinated earlier. However, patients who have received monoclonal antibody or immune plasma treatment need to wait this long. These treatments may render the vaccines ineffective. Therefore, these people need to postpone vaccination for 90 days after treatment.

Researchers reported that people who had previously recovered from Covid-19 and were immunized with mRNA vaccines had more pronounced antibody responses to their first vaccinations than others. This response suggests that a person's acquired natural immunity is the "prime" and the first vaccination is the "boost" for the host's SARS-CoV-2 immune response. While such a model suggests that the second vaccine dose may not be necessary, not all immunologists agree. For now, a second dose of an mRNA vaccine is still recommended.

If a person develops Covid-19 shortly after the first dose of an mRNA vaccine, should the scheduled second dose still be given?

The vaccine begins to produce protective immunity 10 – 14 days after the first dose. Consequently, it is not surprising that some people develop Covid-19 shortly after the first dose. Naturally, these people wonder whether they need to receive the second dose as originally scheduled.

The current recommendation is that people with infection should wait until they have recovered from the acute illness and completed their quarantine period. These recommendations apply both to those who develop Covid-19 before the first dose and to those who develop it after the first dose.

Should a patient who received antibody treatment, immune plasma treatment, or both for Covid-19 be vaccinated?

Not immediately, but yes at the end of treatment. Monoclonal antibody treatment and immune plasma treatment for Covid-19 interfere with the immune response that the vaccine would produce, reducing the effects of the treatments. Therefore, postponing vaccination plans for 90 days is recommended.

How do vaccines affect a person's assessment and diagnostic testing for possible Covid-19?

Covid-19 vaccines will not affect the results of PCR or antigen tests for the disease. Vaccines produce antibodies against SARS-CoV-2 that target the spike protein. Some current serological tests look for this antibody; others do not.

Physicians should report a Covid-19 case occurring after two vaccine doses to the local health ministry.

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