Results
315 The lack of boosting of IgM was likely related to an expected class switching to IgG, observed
316 with increasing IgG titers observed following the boost. Conversely, the lack of boosting of IgA
317 observed across all women in this study was unexpected. This lack of IgA augmentation may be
318 related to the intramuscular administration of the vaccine, which triggers a robust induction of
319 systemic, but not mucosal, antibodies. However, higher levels of IgA were noted after the boost
320 in pregnant Moderna recipients, potentially attributable to enhanced class switching following a
321 longer boosting interval. Robust IgG levels were noted in all vaccinees, and vaccine-induced IgG
322 was transferred across the placenta to the fetus, as has been noted in the setting of influenza,
pertussis, and other vaccination in pregnancy16–18 323 . The presence of neutralizing antibody transfer
324 in nearly all cords, and improved transfer with increased time from vaccination, points to the
325 promise of mRNA vaccine-induced delivery of immunity to neonates. Transfer would perhaps be
326 optimized if vaccination is administered earlier during gestation, though this needs to be directly
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327 examined in future studies. While the transferred levels of IgA through breastmilk did not
328 increase with boosting, IgG transfer increased significantly with boost, resulting in the delivery
329 of high levels of IgG to the neonate through breastmilk. Importantly, emerging data point to a
330 critical role for breastmilk IgG in neonatal immunity against several other vaccinatable viral
pathogens including HIV, RSV, and influenza19–21 331 . In contrast, IgA dominates breastmilk
profiles in natural SARS-CoV-2 infection22 332 . The different isotype transfer profile for breastmilk
333 (IgG in vaccine, IgA in natural infection) likely reflects differences in antibody profile
334 programming across mucosally-acquired natural SARS-CoV-2 infection versus intra-muscular
335 vaccination. Whether breastmilk IgG or IgA will be more critical for neonatal protection remains
336 unclear.
337
338 Based on what is known about other vaccines, the amount of maternal IgG transferred across the
placenta to the cord is likely to differ by trimester of vaccination16,17 339 . Based on data from natural
infection14 340 , qualitative changes in vaccine-elicited antibodies are likely to profoundly alter
341 antibody transfer, and immunization with a de novo antigen earlier in pregnancy is likely to
342 increase placental transfer. Understanding vaccine-induced antibody transfer kinetics across all
343 pregnancy trimesters will be an important direction for future research. While timing maternal
344 COVID-19 vaccination may not be possible during this phase of the pandemic, understanding
345 optimal timing of vaccination to augment neonatal humoral immunity remains important. Unlike
346 vaccines that aim to boost pre-existing antibodies (e.g influenza and pertussis vaccines), optimal
347 timing for de novo vaccine administration remains unclear. Thus, as the prevalence of SARS348 CoV-2 community spread decreases, different factors such as optimizing neonatal immunity via
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349 placental or breastmilk transfer may be weighted more heavily to inform future vaccine
350 deployment.
351
352
353 Following EUA for the COVID-19 mRNA vaccines, safety information has been tracked by the
354 CDC using the V-safe smartphone application. Consistent with our observations, the V-safe data
355 indicate no significant differences in post-vaccination reactions in pregnant vs. non-pregnant
women aged 16-54 years23 356 . While the side effect profile of pregnant women receiving the
357 COVID-19 vaccines was not significantly different from non-pregnant women, the relatively
358 high incidence of fever (up to 32% following the second dose), raises a theoretical concern for
pregnant recipients24,25, although the level of risk remains controversial26 359 .
360
361 Clinical Implications
362 When considering vaccination in pregnancy, evidence regarding maternal and fetal benefit, as
363 well as potential maternal and fetal harm and effects on pregnancy outcomes should be weighed
364 carefully. While the absolute risk of severe COVID-19 is low in pregnant women, pregnancy is a
risk factor for severe disease27,28 365 . There are well-documented maternal, neonatal, and obstetric
risks of SARS-CoV-2 infection during pregnancy29–33 366 . These data provide a compelling
367 argument that COVID-19 mRNA vaccines induce similar humoral immunity in pregnant and
368 lactating women as in the non-pregnant population. These data do not elucidate potential risks to
369 the fetus.
370
371 Research Implications
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372 Future studies, in larger populations spanning vaccine administration across all three trimesters
373 and evaluating associated fetal/neonatal transfer of IgG via cord and breastmilk, may enhance
374 our ability to develop evidence-based recommendations for the administration of vaccines, and
375 particularly different platforms, during pregnancy. While limited evidence of antibody376 dependent enhancement has been observed in the context of pre-existing natural or vaccine
377 immunity in adults, future studies should carefully examine the impact of transferred immunity
378 on infant immune response, and should define the optimal window for immunization to empower
379 infants with robust immunity.
380
381 Strengths and Limitations
382 This study was limited by the select population of primarily healthcare workers from one US
383 city, the focused time frame with limited number of delivered participants, inability to assess
384 persistent immunity, and the exclusive focus on antibody titers rather than T cell-driven or other
385 functional immunity. Future work examining T cells and other immune functions may provide
386 additional insights on mRNA vaccine-induced immunity in pregnancy and lactation. The
387 strengths of this work include: the provision of longitudinal data profiling vaccine-induced
388 immune response across contemporaneously-recruited pregnant, lactating, and non-pregnant
389 women; the ability to compare vaccine-induced IgG titers to those from prior SARS-CoV-2
390 infection; and the inclusion of 10 maternal/neonatal dyads, demonstrating transfer of vaccine391 induced IgG (including NAbs) to the neonate, with improved cord titers achieved as interval
392 from vaccination increased.
393 Conclusions
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394 COVID-19 vaccination in pregnancy and lactation generated robust humoral immunity similar to
395 that observed in non-pregnant women with similar side effect profiles. While humoral immune
396 response and side effects are only two of many considerations for pregnant women and their care
397 providers in weighing whether or not to be vaccinated against COVID-19 in pregnancy, these
398 data confirm that the COVID-19 mRNA vaccines result in comparable humoral immune
399 responses in pregnant and lactating women to those observed in non-pregnant populations.
400
401 ACKNOWLEDGMENTS: We thank Dr. Anjali Kaimal and Dr. Jeff Ecker for their assistance
402 starting the COVID-19 Pregnancy Biorepository at Massachusetts General Hospital.
